Traffic in life, "Jornada d'Investigadors Predoctorals Interdisciplinària" (JIPI), February 6th, 2014

1. Traffic
in
life
Dept. d’Estructura i Constituents de la Matèria,
Facultat de Física (UB)
U David Oriola Santandreu
B
Ph.D. advisor: Jaume Casademunt
UNIVERSITAT DE BARCELONA
Cell cover, 141 (2), 2010

2. Intracellular transport

3. Intracellular transport
Soma
Axon
Synaptic
terminal

4. Intracellular transport
Soma
Axon
Synaptic
terminal
Organelle transport

5. that can affect microtubule-based axonal transport.
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
NATURE REVIEWS | !"#$%&'("!'") © 2013 Macmillan Publishers Universitaire de Québec,
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the They have a tubular structure (25 nm in are composed of many !- and "-tubulin which undergo continuous polymerization at the centrosome1. Microtubules in axons (but not in dendrites): their slower minus end (at which !-tubulin is exposed) body, whereas their faster growing plus "-tubulin is exposed) points towards the axon Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
Intracellular transport
Soma
Axon
at the centrosome1. Microtubules are polar-ized
in axons (but not in dendrites): their slower growing
Synaptic
terminal
Organelle transport
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
Axonal transport is an essential process in neurons
because of the extreme polarity and size of these cells.
Indeed, despite having axons of more than 1 metre in
length, human spinal motor neurons, like other types
of neurons, require efficient communication between
their cell body and axon tip. Axonal transport keeps
axons and nerve terminals supplied with proteins,
lipids and mitochondria, and clears recycled or mis-folded
proteins to avoid the build-up of toxic aggre-gates1.
Apart from its role in neuronal metabolism, axonal
transport is crucial for intracellular neural transmission
and allows the neuron to respond effectively to trophic
signals or stress insults1.
Impairment of axonal transport has recently emerged
as a common factor in several neurodegenerative
disorders1. Here, we review the current state of knowl-edge
about axonal transport defects that are associated
with such disorders, with a specific focus on the mecha-nisms
that can affect microtubule-based axonal transport.
Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
at the centrosome1. Microtubules are polar-ized
in axons (but not in dendrites): their slower growing
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
are stabilized by microtubule-associated proteins such
as tau. Microtubules in the axon essentially form tracks
along which various cargoes can be transported by various
motor proteins.
The various cargoes that are transported along micro-tubules
in axons (TABLE!1) move in a saltatory fashion,
exhibiting periods of rapid movements, pauses and
directional switches. Filamentous cargoes, such as neuro-filaments,
exhibit long periods of rest (spending on aver-age
73% of the time pausing) and movements mainly in
an anterograde direction (that is, towards the cell body)
at 0.23 #m per second2,3. By contrast, vesicular cargoes,
such as lysosomes, show frequent pausing and direc-tional
switches, and other vesicular structures such as
autophagosomes exhibit persistent movements (they only
pause 12% of the time) in a mainly retrograde direction
(that is, away from the cell body) at 0.46 #m per second4.
Thus, the average transport velocity of a particular cargo
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
Neurofilaments
Neurofilaments are
components of the neuronal
cytoskeleton. They are
intermediate filaments with a
diameter of 10 nm and are
composed of three subunits:
the neurofilament light,
medium and heavy chains.
Axonal transport deficits and
neurodegenerative diseases
Stéphanie Millecamps1 and Jean-Pierre Julien2
!"#$%&'$()(*+,(-.$%&',//0/&%($%&.#12%$(23(2%4&.,//,#(&/2.4(&.(&52.(-#('%0'-&/(32%($+,(
6&-.$,.&.',(&.7(30.'$-2.(23(&(.,0%2.8(!.$,%24%&7,(&52.&/($%&.#12%$(+&#(&(%2/,(-.(
#011/9-.4(1%2$,-.#(&.7(/-1-7#($2($+,(7-#$&/(#9.&1#,(&.7(6-$2'+2.7%-&(32%(/2'&/(,.,%49(
%,:0-%,6,.$#;(<+,%,&#(%,$%24%&7,($%&.#12%$(-#(-.=2/=,7(-.($+,('/,&%&.',(23(6-#32/7,7(&.7(
&44%,4&$,7(1%2$,-.#(3%26($+,(&52.(&.7($+,(-.$%&',//0/&%($%&.#12%$(23(7-#$&/($%21+-'(#-4.&/#(
$2($+,(#26&8(!52.&/($%&.#12%$('&.(",(&33,'$,7("9(&/$,%&$-2.#($2(=&%-20#('2612.,.$#(23($+,(
$%&.#12%$(6&'+-.,%98(>,%,;(<,(%,=-,<($+,('0%%,.$(#$&$,(23(?.2</,74,(&"20$(&52.&/(
$%&.#12%$(7,3,'$#($+&$(6-4+$('2.$%-"0$,($2($+,(1&$+24,.,#-#(23(1&%$-'0/&%(
.,0%27,4,.,%&$-=,(7-#,&#,#8
1Centre de Recherche de
l’Institut du Cerveau et de la
Moelle épinière,
INSERM UMR_S975, CNRS
UMR7225, Université Pierre
et Marie Curie,
Hôpital de la Pitié-Salpêtrière,
47–83 boulevard de
l’Hôpital, 75013 Paris,
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
!"#$"%&
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
© 2013 Macmillan Publishers Limited. All rights reserved

6. MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
that can affect microtubule-based axonal transport.
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
NATURE REVIEWS | !"#$%&'("!'") © 2013 Macmillan Publishers Universitaire de Québec,
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the They have a tubular structure (25 nm in are composed of many !- and "-tubulin which undergo continuous polymerization at the centrosome1. Microtubules in axons (but not in dendrites): their slower minus end (at which !-tubulin is exposed) body, whereas their faster growing plus "-tubulin is exposed) points towards the axon Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
Intracellular transport
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively at the centrosome1. transported Microtubules to either axons are polar-ized
or dendrites. In addition, some specific
mRNAs are transported in axons (but to dendrites not in dendrites): for local their translation. slower growing
Proteins of the kinesin superfamily
participate in selective transport by using adaptor or scaffolding proteins to recognize and bind
cargoes. The molecular components of RNA-transporting granules have been identified, and it is
becoming clear how cargoes are directed to axons and dendrites by kinesin superfamily proteins.
Here we discuss the molecular mechanisms of directional axonal and dendritic transport with
specific emphasis on the role of motor proteins and their mechanisms of cargo recognition.
Nobutaka Hirokawa* and Reiko Takemura‡
"#$%&'(%)!)*+%&'(,--.-'&)%&'+$/0&%)1$)2.+3'4,+%'-)20&)+,.&0+'-)40&/506,+,$1$7)2.+(%10+)'+3)$.&818'-9
:'+;)/&0%,1+$)'&,)$,-,(%18,-;)%&'+$/0&%,3)%0),1%5,&)'<0+$)0&)3,+3&1%,$9)*+)'331%10+7)$04,)$/,(121(
4=>"$)'&,)%&'+$/0&%,3)%0)3,+3&1%,$)20&)-0('-)%&'+$-'%10+9)?&0%,1+$)02)%5,)@1+,$1+)$./,&2'41-;
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
1(1/'%,)1+)$,-,(%18,)%&'+$/0&%)#;).$1+6)'3'/%0&)0&)$('220-31+6)/&0%,1+$)%0)&,(06+1A,)'+3)#1+3
60,$9)B5,)40-,(.-'&)(04/0+,+%$)02)=>"C%&'+$/0&%1+6)6&'+.-,$)5'8,)#,,+)13,+%121,37)'+3)1%)1$
041+6)(-,'&)50D)('&60,$)'&,)31&,(%,3)%0)'<0+$)'+3)3,+3&1%,$)#;)@1+,$1+)$./,&2'41-;)/&0%,1+$9
E,&,)D,)31$(.$$)%5,)40-,(.-'&)4,(5'+1$4$)02)31&,(%10+'-)'<0+'-)'+3)3,+3&1%1()%&'+$/0&%)D1%5
A neuron has a highly polarized structure. A typical neu-ron
121(),4/5'$1$)0+)%5,)&0-,)02)40%0&)/&0%,1+$)'+3)%5,1&)4,(5'+1$4$)02)('&60)&,(06+1%10+9
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
that are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
axon in membranous organelles or protein complexes1.
Most dendritic proteins are also transported from the cell
body, but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
In the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
which membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
hollow cylinder that is made of a polymer of !- and
"-tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
slow-growing ‘minus end’6.Microtubules in axons and
distal dendrites are unipolar,with the plus end pointing
away from the cell body7,8. However, the microtubules
in proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
end of microtubules (‘plus-end-directed motors’) and
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively, whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour.This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
MOLECULAR MOTOR
SUPERFAMILIES
Kinesin and dynein superfamily
proteins move along
microtubules, and myosin
superfamily proteins move
along actin filaments by ATP
hydrolysis.
*Department of Cell Biology
and Anatomy,Graduate
School ofMedicine,
University of Tokyo,
Hongo 7-3-1, Bunkyo-ku,
Tokyo 113-0033, Japan.
‡Okinaka Memorial
Institute for Medical
Research,Toranomon 2-2-2,
Minato-ku,Tokyo 105-8470,
Japan.
Correspondence to N.H.
e-mail: hirokawa@
m.u-tokyo.ac.jp
doi:10.1038/nrn1624
Published online
15 February 2005
NATURE REVIEWS | NEUROSCIENCE ADVANCE ONLINE PUBLICATION | 1
©!!""#!Nature Publishing Group!
VOLUME 6 ! MARCH 2005 ! 201
neuron has a highly polarized structure. A typical neu-ron
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
membranous organelles or protein complexes1.
dendritic proteins are also transported from the cell
but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
cylinder that is made of a polymer of !- and
tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
growing ‘minus end’6.Microtubules in axons and
dendrites are unipolar,with the plus end pointing
from the cell body7,8. However,the microtubules
proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
microtubules (‘plus-end-directed motors’) and
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively,whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour. This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
R E V I E W S
Nature Reviews Neuroscience | AOP, published online 15 February 2005; doi:10.1038/nrn1624
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively transported to either axons or dendrites. In addition, some specific
mRNAs are transported to dendrites for local translation. Proteins of the kinesin superfamily
Soma
Axon
Synaptic
terminal
Organelle transport
Axonal transport is an essential process in neurons
because of the extreme polarity and size of these cells.
Indeed, despite having axons of more than 1 metre in
length, human spinal motor neurons, like other types
of neurons, require efficient communication between
their cell body and axon tip. Axonal transport keeps
axons and nerve terminals supplied with proteins,
lipids and mitochondria, and clears recycled or mis-folded
proteins to avoid the build-up of toxic aggre-gates1.
Apart from its role in neuronal metabolism, axonal
transport is crucial for intracellular neural transmission
and allows the neuron to respond effectively to trophic
signals or stress insults1.
Impairment of axonal transport has recently emerged
as a common factor in several neurodegenerative
disorders1. Here, we review the current state of knowl-edge
about axonal transport defects that are associated
with such disorders, with a specific focus on the mecha-nisms
that can affect microtubule-based axonal transport.
Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
at the centrosome1. Microtubules are polar-ized
in axons (but not in dendrites): their slower growing
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
are stabilized by microtubule-associated proteins such
as tau. Microtubules in the axon essentially form tracks
along which various cargoes can be transported by various
motor proteins.
The various cargoes that are transported along micro-tubules
in axons (TABLE!1) move in a saltatory fashion,
exhibiting periods of rapid movements, pauses and
directional switches. Filamentous cargoes, such as neuro-filaments,
exhibit long periods of rest (spending on aver-age
73% of the time pausing) and movements mainly in
an anterograde direction (that is, towards the cell body)
at 0.23 #m per second2,3. By contrast, vesicular cargoes,
such as lysosomes, show frequent pausing and direc-tional
switches, and other vesicular structures such as
autophagosomes exhibit persistent movements (they only
pause 12% of the time) in a mainly retrograde direction
(that is, away from the cell body) at 0.46 #m per second4.
Thus, the average transport velocity of a particular cargo
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
Neurofilaments
Neurofilaments are
components of the neuronal
cytoskeleton. They are
intermediate filaments with a
diameter of 10 nm and are
composed of three subunits:
the neurofilament light,
medium and heavy chains.
Axonal transport deficits and
neurodegenerative diseases
Stéphanie Millecamps1 and Jean-Pierre Julien2
!"#$%&'$()(*+,(-.$%&',//0/&%($%&.#12%$(23(2%4&.,//,#(&/2.4(&.(&52.(-#('%0'-&/(32%($+,(
6&-.$,.&.',(&.7(30.'$-2.(23(&(.,0%2.8(!.$,%24%&7,(&52.&/($%&.#12%$(+&#(&(%2/,(-.(
#011/9-.4(1%2$,-.#(&.7(/-1-7#($2($+,(7-#$&/(#9.&1#,(&.7(6-$2'+2.7%-&(32%(/2'&/(,.,%49(
%,:0-%,6,.$#;(<+,%,&#(%,$%24%&7,($%&.#12%$(-#(-.=2/=,7(-.($+,('/,&%&.',(23(6-#32/7,7(&.7(
&44%,4&$,7(1%2$,-.#(3%26($+,(&52.(&.7($+,(-.$%&',//0/&%($%&.#12%$(23(7-#$&/($%21+-'(#-4.&/#(
$2($+,(#26&8(!52.&/($%&.#12%$('&.(",(&33,'$,7("9(&/$,%&$-2.#($2(=&%-20#('2612.,.$#(23($+,(
$%&.#12%$(6&'+-.,%98(>,%,;(<,(%,=-,<($+,('0%%,.$(#$&$,(23(?.2</,74,(&"20$(&52.&/(
$%&.#12%$(7,3,'$#($+&$(6-4+$('2.$%-"0$,($2($+,(1&$+24,.,#-#(23(1&%$-'0/&%(
.,0%27,4,.,%&$-=,(7-#,&#,#8
1Centre de Recherche de
l’Institut du Cerveau et de la
Moelle épinière,
INSERM UMR_S975, CNRS
UMR7225, Université Pierre
et Marie Curie,
Hôpital de la Pitié-Salpêtrière,
47–83 boulevard de
l’Hôpital, 75013 Paris,
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
!"#$"%&
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
© 2013 Macmillan Publishers Limited. All rights reserved

7. MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
that can affect microtubule-based axonal transport.
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
NATURE REVIEWS | !"#$%&'("!'") © 2013 Macmillan Publishers Universitaire de Québec,
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the They have a tubular structure (25 nm in are composed of many !- and "-tubulin which undergo continuous polymerization at the centrosome1. Microtubules in axons (but not in dendrites): their slower minus end (at which !-tubulin is exposed) body, whereas their faster growing plus "-tubulin is exposed) points towards the axon Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
Intracellular transport
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively at the centrosome1. transported Microtubules to either axons are polar-ized
or dendrites. In addition, some specific
mRNAs are transported in axons (but to dendrites not in dendrites): for local their translation. slower growing
Proteins of the kinesin superfamily
participate in selective transport by using adaptor or scaffolding proteins to recognize and bind
cargoes. The molecular components of RNA-transporting granules have been identified, and it is
becoming clear how cargoes are directed to axons and dendrites by kinesin superfamily proteins.
Here we discuss the molecular mechanisms of directional axonal and dendritic transport with
specific emphasis on the role of motor proteins and their mechanisms of cargo recognition.
Nobutaka Hirokawa* and Reiko Takemura‡
"#$%&'(%)!)*+%&'(,--.-'&)%&'+$/0&%)1$)2.+3'4,+%'-)20&)+,.&0+'-)40&/506,+,$1$7)2.+(%10+)'+3)$.&818'-9
:'+;)/&0%,1+$)'&,)$,-,(%18,-;)%&'+$/0&%,3)%0),1%5,&)'<0+$)0&)3,+3&1%,$9)*+)'331%10+7)$04,)$/,(121(
4=>"$)'&,)%&'+$/0&%,3)%0)3,+3&1%,$)20&)-0('-)%&'+$-'%10+9)?&0%,1+$)02)%5,)@1+,$1+)$./,&2'41-;
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
1(1/'%,)1+)$,-,(%18,)%&'+$/0&%)#;).$1+6)'3'/%0&)0&)$('220-31+6)/&0%,1+$)%0)&,(06+1A,)'+3)#1+3
60,$9)B5,)40-,(.-'&)(04/0+,+%$)02)=>"C%&'+$/0&%1+6)6&'+.-,$)5'8,)#,,+)13,+%121,37)'+3)1%)1$
041+6)(-,'&)50D)('&60,$)'&,)31&,(%,3)%0)'<0+$)'+3)3,+3&1%,$)#;)@1+,$1+)$./,&2'41-;)/&0%,1+$9
E,&,)D,)31$(.$$)%5,)40-,(.-'&)4,(5'+1$4$)02)31&,(%10+'-)'<0+'-)'+3)3,+3&1%1()%&'+$/0&%)D1%5
A neuron has a highly polarized structure. A typical neu-ron
121(),4/5'$1$)0+)%5,)&0-,)02)40%0&)/&0%,1+$)'+3)%5,1&)4,(5'+1$4$)02)('&60)&,(06+1%10+9
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
that are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
axon in membranous organelles or protein complexes1.
Most dendritic proteins are also transported from the cell
body, but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
In the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
which membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
hollow cylinder that is made of a polymer of !- and
"-tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
slow-growing ‘minus end’6.Microtubules in axons and
distal dendrites are unipolar,with the plus end pointing
away from the cell body7,8. However, the microtubules
in proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
end of microtubules (‘plus-end-directed motors’) and
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively, whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour.This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
MOLECULAR MOTOR
SUPERFAMILIES
Kinesin and dynein superfamily
proteins move along
microtubules, and myosin
superfamily proteins move
along actin filaments by ATP
hydrolysis.
*Department of Cell Biology
and Anatomy,Graduate
School ofMedicine,
University of Tokyo,
Hongo 7-3-1, Bunkyo-ku,
Tokyo 113-0033, Japan.
‡Okinaka Memorial
Institute for Medical
Research,Toranomon 2-2-2,
Minato-ku,Tokyo 105-8470,
Japan.
Correspondence to N.H.
e-mail: hirokawa@
m.u-tokyo.ac.jp
doi:10.1038/nrn1624
Published online
15 February 2005
NATURE REVIEWS | NEUROSCIENCE ADVANCE ONLINE PUBLICATION | 1
©!!""#!Nature Publishing Group!
VOLUME 6 ! MARCH 2005 ! 201
neuron has a highly polarized structure. A typical neu-ron
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
membranous organelles or protein complexes1.
dendritic proteins are also transported from the cell
but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
cylinder that is made of a polymer of !- and
tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
growing ‘minus end’6.Microtubules in axons and
dendrites are unipolar,with the plus end pointing
from the cell body7,8. However,the microtubules
proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
microtubules (‘plus-end-directed motors’) and
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively,whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour. This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
R E V I E W S
Nature Reviews Neuroscience | AOP, published online 15 February 2005; doi:10.1038/nrn1624
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively transported to either axons or dendrites. In addition, some specific
mRNAs are transported to dendrites for local translation. Proteins of the kinesin superfamily
Soma
Axon
Synaptic
terminal
Organelle transport
Axonal transport is an essential process in neurons
because of the extreme polarity and size of these cells.
Indeed, despite having axons of more than 1 metre in
length, human spinal motor neurons, like other types
of neurons, require efficient communication between
their cell body and axon tip. Axonal transport keeps
axons and nerve terminals supplied with proteins,
lipids and mitochondria, and clears recycled or mis-folded
proteins to avoid the build-up of toxic aggre-gates1.
Apart from its role in neuronal metabolism, axonal
transport is crucial for intracellular neural transmission
and allows the neuron to respond effectively to trophic
signals or stress insults1.
Impairment of axonal transport has recently emerged
as a common factor in several neurodegenerative
disorders1. Here, we review the current state of knowl-edge
about axonal transport defects that are associated
with such disorders, with a specific focus on the mecha-nisms
that can affect microtubule-based axonal transport.
Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
at the centrosome1. Microtubules are polar-ized
in axons (but not in dendrites): their slower growing
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
are stabilized by microtubule-associated proteins such
as tau. Microtubules in the axon essentially form tracks
along which various cargoes can be transported by various
motor proteins.
The various cargoes that are transported along micro-tubules
in axons (TABLE!1) move in a saltatory fashion,
exhibiting periods of rapid movements, pauses and
directional switches. Filamentous cargoes, such as neuro-filaments,
exhibit long periods of rest (spending on aver-age
73% of the time pausing) and movements mainly in
an anterograde direction (that is, towards the cell body)
at 0.23 #m per second2,3. By contrast, vesicular cargoes,
such as lysosomes, show frequent pausing and direc-tional
switches, and other vesicular structures such as
autophagosomes exhibit persistent movements (they only
pause 12% of the time) in a mainly retrograde direction
(that is, away from the cell body) at 0.46 #m per second4.
Thus, the average transport velocity of a particular cargo
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
Neurofilaments
Neurofilaments are
components of the neuronal
cytoskeleton. They are
intermediate filaments with a
diameter of 10 nm and are
composed of three subunits:
the neurofilament light,
medium and heavy chains.
Axonal transport deficits and
neurodegenerative diseases
Stéphanie Millecamps1 and Jean-Pierre Julien2
!"#$%&'$()(*+,(-.$%&',//0/&%($%&.#12%$(23(2%4&.,//,#(&/2.4(&.(&52.(-#('%0'-&/(32%($+,(
6&-.$,.&.',(&.7(30.'$-2.(23(&(.,0%2.8(!.$,%24%&7,(&52.&/($%&.#12%$(+&#(&(%2/,(-.(
#011/9-.4(1%2$,-.#(&.7(/-1-7#($2($+,(7-#$&/(#9.&1#,(&.7(6-$2'+2.7%-&(32%(/2'&/(,.,%49(
%,:0-%,6,.$#;(<+,%,&#(%,$%24%&7,($%&.#12%$(-#(-.=2/=,7(-.($+,('/,&%&.',(23(6-#32/7,7(&.7(
&44%,4&$,7(1%2$,-.#(3%26($+,(&52.(&.7($+,(-.$%&',//0/&%($%&.#12%$(23(7-#$&/($%21+-'(#-4.&/#(
$2($+,(#26&8(!52.&/($%&.#12%$('&.(",(&33,'$,7("9(&/$,%&$-2.#($2(=&%-20#('2612.,.$#(23($+,(
$%&.#12%$(6&'+-.,%98(>,%,;(<,(%,=-,<($+,('0%%,.$(#$&$,(23(?.2</,74,(&"20$(&52.&/(
$%&.#12%$(7,3,'$#($+&$(6-4+$('2.$%-"0$,($2($+,(1&$+24,.,#-#(23(1&%$-'0/&%(
.,0%27,4,.,%&$-=,(7-#,&#,#8
1Centre de Recherche de
l’Institut du Cerveau et de la
Moelle épinière,
INSERM UMR_S975, CNRS
UMR7225, Université Pierre
et Marie Curie,
Hôpital de la Pitié-Salpêtrière,
47–83 boulevard de
l’Hôpital, 75013 Paris,
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
!"#$"%&
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
© 2013 Macmillan Publishers Limited. All rights reserved

8. MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
that can affect microtubule-based axonal transport.
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
NATURE REVIEWS | !"#$%&'("!'") © 2013 Macmillan Publishers Universitaire de Québec,
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the They have a tubular structure (25 nm in are composed of many !- and "-tubulin which undergo continuous polymerization at the centrosome1. Microtubules in axons (but not in dendrites): their slower minus end (at which !-tubulin is exposed) body, whereas their faster growing plus "-tubulin is exposed) points towards the axon Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
Intracellular transport
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively at the centrosome1. transported Microtubules to either axons are polar-ized
or dendrites. In addition, some specific
mRNAs are transported in axons (but to dendrites not in dendrites): for local their translation. slower growing
Proteins of the kinesin superfamily
participate in selective transport by using adaptor or scaffolding proteins to recognize and bind
cargoes. The molecular components of RNA-transporting granules have been identified, and it is
becoming clear how cargoes are directed to axons and dendrites by kinesin superfamily proteins.
Here we discuss the molecular mechanisms of directional axonal and dendritic transport with
specific emphasis on the role of motor proteins and their mechanisms of cargo recognition.
Nobutaka Hirokawa* and Reiko Takemura‡
"#$%&'(%)!)*+%&'(,--.-'&)%&'+$/0&%)1$)2.+3'4,+%'-)20&)+,.&0+'-)40&/506,+,$1$7)2.+(%10+)'+3)$.&818'-9
:'+;)/&0%,1+$)'&,)$,-,(%18,-;)%&'+$/0&%,3)%0),1%5,&)'<0+$)0&)3,+3&1%,$9)*+)'331%10+7)$04,)$/,(121(
4=>"$)'&,)%&'+$/0&%,3)%0)3,+3&1%,$)20&)-0('-)%&'+$-'%10+9)?&0%,1+$)02)%5,)@1+,$1+)$./,&2'41-;
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
1(1/'%,)1+)$,-,(%18,)%&'+$/0&%)#;).$1+6)'3'/%0&)0&)$('220-31+6)/&0%,1+$)%0)&,(06+1A,)'+3)#1+3
60,$9)B5,)40-,(.-'&)(04/0+,+%$)02)=>"C%&'+$/0&%1+6)6&'+.-,$)5'8,)#,,+)13,+%121,37)'+3)1%)1$
041+6)(-,'&)50D)('&60,$)'&,)31&,(%,3)%0)'<0+$)'+3)3,+3&1%,$)#;)@1+,$1+)$./,&2'41-;)/&0%,1+$9
E,&,)D,)31$(.$$)%5,)40-,(.-'&)4,(5'+1$4$)02)31&,(%10+'-)'<0+'-)'+3)3,+3&1%1()%&'+$/0&%)D1%5
A neuron has a highly polarized structure. A typical neu-ron
121(),4/5'$1$)0+)%5,)&0-,)02)40%0&)/&0%,1+$)'+3)%5,1&)4,(5'+1$4$)02)('&60)&,(06+1%10+9
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
that are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
axon in membranous organelles or protein complexes1.
Most dendritic proteins are also transported from the cell
body, but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
In the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
which membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
hollow cylinder that is made of a polymer of !- and
"-tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
slow-growing ‘minus end’6.Microtubules in axons and
distal dendrites are unipolar,with the plus end pointing
away from the cell body7,8. However, the microtubules
in proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
end of microtubules (‘plus-end-directed motors’) and
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively, whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour.This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
MOLECULAR MOTOR
SUPERFAMILIES
Kinesin and dynein superfamily
proteins move along
microtubules, and myosin
superfamily proteins move
along actin filaments by ATP
hydrolysis.
*Department of Cell Biology
and Anatomy,Graduate
School ofMedicine,
University of Tokyo,
Hongo 7-3-1, Bunkyo-ku,
Tokyo 113-0033, Japan.
‡Okinaka Memorial
Institute for Medical
Research,Toranomon 2-2-2,
Minato-ku,Tokyo 105-8470,
Japan.
Correspondence to N.H.
e-mail: hirokawa@
m.u-tokyo.ac.jp
doi:10.1038/nrn1624
Published online
15 February 2005
NATURE REVIEWS | NEUROSCIENCE ADVANCE ONLINE PUBLICATION | 1
©!!""#!Nature Publishing Group!
VOLUME 6 ! MARCH 2005 ! 201
neuron has a highly polarized structure. A typical neu-ron
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
membranous organelles or protein complexes1.
dendritic proteins are also transported from the cell
but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
cylinder that is made of a polymer of !- and
tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
growing ‘minus end’6.Microtubules in axons and
dendrites are unipolar,with the plus end pointing
from the cell body7,8. However,the microtubules
proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
microtubules (‘plus-end-directed motors’) and
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively,whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour. This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
R E V I E W S
Nature Reviews Neuroscience | AOP, published online 15 February 2005; doi:10.1038/nrn1624
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively transported to either axons or dendrites. In addition, some specific
mRNAs are transported to dendrites for local translation. Proteins of the kinesin superfamily
Soma
Axon
Synaptic
terminal
Organelle transport
Axonal transport is an essential process in neurons
because of the extreme polarity and size of these cells.
Indeed, despite having axons of more than 1 metre in
length, human spinal motor neurons, like other types
of neurons, require efficient communication between
their cell body and axon tip. Axonal transport keeps
axons and nerve terminals supplied with proteins,
lipids and mitochondria, and clears recycled or mis-folded
proteins to avoid the build-up of toxic aggre-gates1.
Apart from its role in neuronal metabolism, axonal
transport is crucial for intracellular neural transmission
and allows the neuron to respond effectively to trophic
signals or stress insults1.
Impairment of axonal transport has recently emerged
as a common factor in several neurodegenerative
disorders1. Here, we review the current state of knowl-edge
about axonal transport defects that are associated
with such disorders, with a specific focus on the mecha-nisms
that can affect microtubule-based axonal transport.
Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
at the centrosome1. Microtubules are polar-ized
in axons (but not in dendrites): their slower growing
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
are stabilized by microtubule-associated proteins such
as tau. Microtubules in the axon essentially form tracks
along which various cargoes can be transported by various
motor proteins.
The various cargoes that are transported along micro-tubules
in axons (TABLE!1) move in a saltatory fashion,
exhibiting periods of rapid movements, pauses and
directional switches. Filamentous cargoes, such as neuro-filaments,
exhibit long periods of rest (spending on aver-age
73% of the time pausing) and movements mainly in
an anterograde direction (that is, towards the cell body)
at 0.23 #m per second2,3. By contrast, vesicular cargoes,
such as lysosomes, show frequent pausing and direc-tional
switches, and other vesicular structures such as
autophagosomes exhibit persistent movements (they only
pause 12% of the time) in a mainly retrograde direction
(that is, away from the cell body) at 0.46 #m per second4.
Thus, the average transport velocity of a particular cargo
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
Neurofilaments
Neurofilaments are
components of the neuronal
cytoskeleton. They are
intermediate filaments with a
diameter of 10 nm and are
composed of three subunits:
the neurofilament light,
medium and heavy chains.
Axonal transport deficits and
neurodegenerative diseases
Stéphanie Millecamps1 and Jean-Pierre Julien2
!"#$%&'$()(*+,(-.$%&',//0/&%($%&.#12%$(23(2%4&.,//,#(&/2.4(&.(&52.(-#('%0'-&/(32%($+,(
6&-.$,.&.',(&.7(30.'$-2.(23(&(.,0%2.8(!.$,%24%&7,(&52.&/($%&.#12%$(+&#(&(%2/,(-.(
#011/9-.4(1%2$,-.#(&.7(/-1-7#($2($+,(7-#$&/(#9.&1#,(&.7(6-$2'+2.7%-&(32%(/2'&/(,.,%49(
%,:0-%,6,.$#;(<+,%,&#(%,$%24%&7,($%&.#12%$(-#(-.=2/=,7(-.($+,('/,&%&.',(23(6-#32/7,7(&.7(
&44%,4&$,7(1%2$,-.#(3%26($+,(&52.(&.7($+,(-.$%&',//0/&%($%&.#12%$(23(7-#$&/($%21+-'(#-4.&/#(
$2($+,(#26&8(!52.&/($%&.#12%$('&.(",(&33,'$,7("9(&/$,%&$-2.#($2(=&%-20#('2612.,.$#(23($+,(
$%&.#12%$(6&'+-.,%98(>,%,;(<,(%,=-,<($+,('0%%,.$(#$&$,(23(?.2</,74,(&"20$(&52.&/(
$%&.#12%$(7,3,'$#($+&$(6-4+$('2.$%-"0$,($2($+,(1&$+24,.,#-#(23(1&%$-'0/&%(
.,0%27,4,.,%&$-=,(7-#,&#,#8
1Centre de Recherche de
l’Institut du Cerveau et de la
Moelle épinière,
INSERM UMR_S975, CNRS
UMR7225, Université Pierre
et Marie Curie,
Hôpital de la Pitié-Salpêtrière,
47–83 boulevard de
l’Hôpital, 75013 Paris,
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
!"#$"%&
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
© 2013 Macmillan Publishers Limited. All rights reserved
two-headed kinesin
one-headed kinesin

9. MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
that can affect microtubule-based axonal transport.
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
NATURE REVIEWS | !"#$%&'("!'") © 2013 Macmillan Publishers Universitaire de Québec,
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the They have a tubular structure (25 nm in are composed of many !- and "-tubulin which undergo continuous polymerization at the centrosome1. Microtubules in axons (but not in dendrites): their slower minus end (at which !-tubulin is exposed) body, whereas their faster growing plus "-tubulin is exposed) points towards the axon Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
Intracellular transport
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively at the centrosome1. transported Microtubules to either axons are polar-ized
or dendrites. In addition, some specific
mRNAs are transported in axons (but to dendrites not in dendrites): for local their translation. slower growing
Proteins of the kinesin superfamily
participate in selective transport by using adaptor or scaffolding proteins to recognize and bind
cargoes. The molecular components of RNA-transporting granules have been identified, and it is
becoming clear how cargoes are directed to axons and dendrites by kinesin superfamily proteins.
Here we discuss the molecular mechanisms of directional axonal and dendritic transport with
specific emphasis on the role of motor proteins and their mechanisms of cargo recognition.
Nobutaka Hirokawa* and Reiko Takemura‡
"#$%&'(%)!)*+%&'(,--.-'&)%&'+$/0&%)1$)2.+3'4,+%'-)20&)+,.&0+'-)40&/506,+,$1$7)2.+(%10+)'+3)$.&818'-9
:'+;)/&0%,1+$)'&,)$,-,(%18,-;)%&'+$/0&%,3)%0),1%5,&)'<0+$)0&)3,+3&1%,$9)*+)'331%10+7)$04,)$/,(121(
4=>"$)'&,)%&'+$/0&%,3)%0)3,+3&1%,$)20&)-0('-)%&'+$-'%10+9)?&0%,1+$)02)%5,)@1+,$1+)$./,&2'41-;
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
1(1/'%,)1+)$,-,(%18,)%&'+$/0&%)#;).$1+6)'3'/%0&)0&)$('220-31+6)/&0%,1+$)%0)&,(06+1A,)'+3)#1+3
60,$9)B5,)40-,(.-'&)(04/0+,+%$)02)=>"C%&'+$/0&%1+6)6&'+.-,$)5'8,)#,,+)13,+%121,37)'+3)1%)1$
041+6)(-,'&)50D)('&60,$)'&,)31&,(%,3)%0)'<0+$)'+3)3,+3&1%,$)#;)@1+,$1+)$./,&2'41-;)/&0%,1+$9
E,&,)D,)31$(.$$)%5,)40-,(.-'&)4,(5'+1$4$)02)31&,(%10+'-)'<0+'-)'+3)3,+3&1%1()%&'+$/0&%)D1%5
A neuron has a highly polarized structure. A typical neu-ron
121(),4/5'$1$)0+)%5,)&0-,)02)40%0&)/&0%,1+$)'+3)%5,1&)4,(5'+1$4$)02)('&60)&,(06+1%10+9
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
that are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
axon in membranous organelles or protein complexes1.
Most dendritic proteins are also transported from the cell
body, but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
In the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
which membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
hollow cylinder that is made of a polymer of !- and
"-tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
slow-growing ‘minus end’6.Microtubules in axons and
distal dendrites are unipolar,with the plus end pointing
away from the cell body7,8. However, the microtubules
in proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
end of microtubules (‘plus-end-directed motors’) and
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively, whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour.This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
MOLECULAR MOTOR
SUPERFAMILIES
Kinesin and dynein superfamily
proteins move along
microtubules, and myosin
superfamily proteins move
along actin filaments by ATP
hydrolysis.
*Department of Cell Biology
and Anatomy,Graduate
School ofMedicine,
University of Tokyo,
Hongo 7-3-1, Bunkyo-ku,
Tokyo 113-0033, Japan.
‡Okinaka Memorial
Institute for Medical
Research,Toranomon 2-2-2,
Minato-ku,Tokyo 105-8470,
Japan.
Correspondence to N.H.
e-mail: hirokawa@
m.u-tokyo.ac.jp
doi:10.1038/nrn1624
Published online
15 February 2005
NATURE REVIEWS | NEUROSCIENCE ADVANCE ONLINE PUBLICATION | 1
©!!""#!Nature Publishing Group!
VOLUME 6 ! MARCH 2005 ! 201
neuron has a highly polarized structure. A typical neu-ron
comprises a cell body, several short, thick, tapering
dendrites and one long, thin axon.Most of the proteins
are needed in the axon and synaptic terminals are
synthesized in the cell body and transported along the
membranous organelles or protein complexes1.
dendritic proteins are also transported from the cell
but several specific mRNAs are transported into
dendrites to support local protein synthesis2 (BOX 1).
the axon and dendrites,microtubules run in a
longitudinal orientation3,4, and serve as rails along
membranous organelles and macromolecular
complexes can be transported5.A microtubule is a long,
cylinder that is made of a polymer of !- and
tubulins and has a diameter of 25 nm. It has intrinsic
polarity,with a fast-growing ‘plus end’ and an opposite,
growing ‘minus end’6.Microtubules in axons and
dendrites are unipolar,with the plus end pointing
from the cell body7,8. However,the microtubules
proximal dendrites are of mixed polarity8. The orga-nization
of microtubules also differs between axons and
dendrites (BOX 2).
MOLECULAR MOTORS of the kinesin and dynein super-families
move along microtubules. Many kinesin
superfamily proteins (KIFs) move towards the plus
microtubules (‘plus-end-directed motors’) and
participate in ANTEROGRADE TRANSPORT, selectively trans-porting
molecules from the cell body to axons and
dendrites. By contrast, RETROGRADE TRANSPORT, from the
axonal or dendritic terminals to the cell body, is car-ried
out mostly by cytoplasmic dyneins, which are
minus-end-directed motors5,9–12.
Selective transport to axons and dendrites has been
studied from several viewpoints, including which
sequences of selectively transported proteins function as
selective targeting signals, and whether the basic mecha-nism
is one of selective transport or selective retention
(whereby cargoes would be transported to both axons
and dendrites, and selectively eliminated by endocytosis
from the inappropriate destination).However, many
seemingly unrelated sequences have been identified as
targeting signals, and the identification of the targeting
sequences of specific proteins has not always clarified the
underlying sorting mechanisms. Both selective transport
and selective retention seem to occur, depending on the
cargoes involved, but it is not clear how some cargoes are
transported selectively,whereas others are transported
nonselectively.Understanding the mechanisms of sort-ing,
selective transport and recognition is an important
endeavour. This review focuses on recent developments
that relate to the mechanisms of selective transport,with
particular emphasis on the role of KIFs.
R E V I E W S
Nature Reviews Neuroscience | AOP, published online 15 February 2005; doi:10.1038/nrn1624
MOLECULAR MOTORS AND
MECHANISMS OF DIRECTIONAL
TRANSPORT IN NEURONS
Nobutaka Hirokawa* and Reiko Takemura‡
Abstract | Intracellular transport is fundamental for neuronal morphogenesis, function and survival.
Many proteins are selectively transported to either axons or dendrites. In addition, some specific
mRNAs are transported to dendrites for local translation. Proteins of the kinesin superfamily
Soma
Axon
Synaptic
terminal
Organelle transport
Axonal transport is an essential process in neurons
because of the extreme polarity and size of these cells.
Indeed, despite having axons of more than 1 metre in
length, human spinal motor neurons, like other types
of neurons, require efficient communication between
their cell body and axon tip. Axonal transport keeps
axons and nerve terminals supplied with proteins,
lipids and mitochondria, and clears recycled or mis-folded
proteins to avoid the build-up of toxic aggre-gates1.
Apart from its role in neuronal metabolism, axonal
transport is crucial for intracellular neural transmission
and allows the neuron to respond effectively to trophic
signals or stress insults1.
Impairment of axonal transport has recently emerged
as a common factor in several neurodegenerative
disorders1. Here, we review the current state of knowl-edge
about axonal transport defects that are associated
with such disorders, with a specific focus on the mecha-nisms
that can affect microtubule-based axonal transport.
Before doing so, we outline the various components and
mechanisms that control such transport.
!"#$%&'(')*+(,-*./,0%1,)/&$,1-2%$&
Microtubules are the main component of the cytoskeleton.
They have a tubular structure (25 nm in diameter) and
are composed of many !- and "-tubulin heterodimers,
which undergo continuous polymerization and depo-lymerization
at the centrosome1. Microtubules are polar-ized
in axons (but not in dendrites): their slower growing
minus end (at which !-tubulin is exposed) faces the cell
body, whereas their faster growing plus end (at which
"-tubulin is exposed) points towards the axon tips. They
are stabilized by microtubule-associated proteins such
as tau. Microtubules in the axon essentially form tracks
along which various cargoes can be transported by various
motor proteins.
The various cargoes that are transported along micro-tubules
in axons (TABLE!1) move in a saltatory fashion,
exhibiting periods of rapid movements, pauses and
directional switches. Filamentous cargoes, such as neuro-filaments,
exhibit long periods of rest (spending on aver-age
73% of the time pausing) and movements mainly in
an anterograde direction (that is, towards the cell body)
at 0.23 #m per second2,3. By contrast, vesicular cargoes,
such as lysosomes, show frequent pausing and direc-tional
switches, and other vesicular structures such as
autophagosomes exhibit persistent movements (they only
pause 12% of the time) in a mainly retrograde direction
(that is, away from the cell body) at 0.46 #m per second4.
Thus, the average transport velocity of a particular cargo
depends on the time that the cargo spends pausing. As
neurofilament proteins move at a faster transport rate
when axons are devoid of pre-existing neurofilament
structures in!vivo, one of the key determinants that
curbs the axonal transport of cytoskeleton components
is the density of the stationary cytoskeletal network in
the axons5. The transport of mitochondria and lysosomes
is also dependent on cytoskeletal organization6.
For convenience, axonal transport can be divided
into two categories: fast axonal transport, which is
responsible for moving membrane-bound organelles
(vesicles and mitochondria), and slow axonal trans-port,
which drives the movement of cytoplasmic pro-teins
(including various enzymes) and cytoskeletal
Neurofilaments
Neurofilaments are
components of the neuronal
cytoskeleton. They are
intermediate filaments with a
diameter of 10 nm and are
composed of three subunits:
the neurofilament light,
medium and heavy chains.
Axonal transport deficits and
neurodegenerative diseases
Stéphanie Millecamps1 and Jean-Pierre Julien2
!"#$%&'$()(*+,(-.$%&',//0/&%($%&.#12%$(23(2%4&.,//,#(&/2.4(&.(&52.(-#('%0'-&/(32%($+,(
6&-.$,.&.',(&.7(30.'$-2.(23(&(.,0%2.8(!.$,%24%&7,(&52.&/($%&.#12%$(+&#(&(%2/,(-.(
#011/9-.4(1%2$,-.#(&.7(/-1-7#($2($+,(7-#$&/(#9.&1#,(&.7(6-$2'+2.7%-&(32%(/2'&/(,.,%49(
%,:0-%,6,.$#;(<+,%,&#(%,$%24%&7,($%&.#12%$(-#(-.=2/=,7(-.($+,('/,&%&.',(23(6-#32/7,7(&.7(
&44%,4&$,7(1%2$,-.#(3%26($+,(&52.(&.7($+,(-.$%&',//0/&%($%&.#12%$(23(7-#$&/($%21+-'(#-4.&/#(
$2($+,(#26&8(!52.&/($%&.#12%$('&.(",(&33,'$,7("9(&/$,%&$-2.#($2(=&%-20#('2612.,.$#(23($+,(
$%&.#12%$(6&'+-.,%98(>,%,;(<,(%,=-,<($+,('0%%,.$(#$&$,(23(?.2</,74,(&"20$(&52.&/(
$%&.#12%$(7,3,'$#($+&$(6-4+$('2.$%-"0$,($2($+,(1&$+24,.,#-#(23(1&%$-'0/&%(
.,0%27,4,.,%&$-=,(7-#,&#,#8
1Centre de Recherche de
l’Institut du Cerveau et de la
Moelle épinière,
INSERM UMR_S975, CNRS
UMR7225, Université Pierre
et Marie Curie,
Hôpital de la Pitié-Salpêtrière,
47–83 boulevard de
l’Hôpital, 75013 Paris,
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
!"#$"%&
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
France.
2Centre de Recherche du
Centre Hospitalier
Universitaire de Québec,
Department of Psychiatry
and Neuroscience,
Laval University,
2705 Boulevard Laurier,
Quebec, Quebec City,
G1V4G2, Canada.
Correspondence to J.-P.J.!
e-mail: jean-pierre.julien@
crchul.ulaval.ca
doi:10.1038/nrn3380
Published online 30 January
2013
NATURE REVIEWS | !"#$%&'("!'") VOLUME 14 | MARCH 2013 | 343
© 2013 Macmillan Publishers Limited. All rights reserved
two-headed kinesin
one-headed kinesin
How do kinesins behave
in front of obstacles?

11. +
-

12. +
-

13. +
-

14. +
-

15. +
-

16. +
-

17. +
-
- + - +