6. ➢ Dystonia is characterized by abnormalities in the control of movement
➢ Involuntary muscle contractions causing twisting movements and abnormal postures
➢ Associated with overflow muscle activation
➢ Dystonic syndromes can be roughly divided into two types, primary and secondary.
➢ Primary dystonia develop spontaneously apparent symptoms e.g. tremor and twisting
movement
➢ Secondary dystonia associated with primary dystonia along with neurodegeneration
including juvenile Parkinson’s disease
Adult-onset focal forms: writer’s cramp
Childhood onset focal forms Cervical dystonia
Dystonia musculorum
What is dystonia:
7. Time line of gene discoveries for isolated and combined forms of dystonia
Timeline and classification of dystonia:
C. Klein et al 2014
➢ Isolated dystonia is when dystonia is the only motor feature with the exception of tremor.
➢ Combined dystonia is used when another movement disorder such as parkinsonism or
myoclonus is also present.
➢ Myoclonus dystonia includes the rapid contractions or muscle jerk along with neurological
and psychiatric issues.
➢ The paroxysmal forms of dystonia/dyskinesias present with a mixed pattern of hyperkinetic
movement disorders.
8. Genetic features , mode of inheritance and molecular
genetic linkage of gene locus to identify specific form
of dystonia:
11. DYT5 dystonia
DYT1 dystonia
DYT12 dystonia
DYT11 dystonia
DYT8 dystonia
DYT3 dystonia
➢ Mutations in GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) impair dopamine synthesis in DYT5 dystonia
➢ Mutations in the α3 subunit of the Na+ /K+ ATPase (ATP1A3) cause rapid-onset dystonia parkinsonism (DYT12)
➢ Mutations in ε-sarcoglycan, probably normally found at the plasma membrane of neurons, cause myoclonus dystonia (DYT11)
➢ Mutations in myofibrillogenesis regulator 1 (MR-1), a putative detoxifying enzyme, cause paroxysmal non-kinesigenic dyskinesia (DYT8)
➢ A general transcription factor, TAF1 is mutated in X-linked dystonia parkinsonism (DYT3).
Xandra O. Breakefield et. al. 2008
Changes in proteins that cause dystonia:
12. Isolated dystonia:
➢ Typically begin in childhood (mean age 13 years, range 1–28 years)
➢ Twisting of an arm or leg, and progression to involve other limbs and torso, but usually not the face and neck
➢ A 3-base pair deletion (GAG) in the coding region of the TOR1A gene
➢ TOR1 Aassociated dystonia is inherited in an autosomal dominant fashion with reduced penetrance (only about
30% of mutant gene carriers are affected)
➢ Mutations in TorsinA have been shown to disturb the endoplasmic reticulum, the nuclear envelope, and/or
cytoskeletal dynamics.
TOR1A DYT1:
DYT-THAP1:
➢ Adolescent-onset dystonia with mixed phenotype (mean 19 years; range 5–38 years)
➢ Mutation in THAP domain containing, apoptosis associated protein 1
➢ Some phenotypic features overlap with TOR1A-associated dystonia, but there is more prominent cranial involvement,
especially in muscles of the lung, larynx and face
Isolated dystonia refers to dystonia with or without tremor but without other neurological symptom
13. Combined dystonia:
Clinical features of dystonia are combined with another movement disorder, most commonly parkinsonism or myoclonus
DYT-GCHI and DYT-TH: dopa-responsive dystonia:
➢ Early onset, generalized by hypotonia and proximal weakness, and association with psychiatric abnormalities.
➢ Mutations in single both tyrosine hydroxylase (TH) gene and GTP cyclohydrolase I (GCHI) gene causes dopa-
responsive dystonia.
➢ Biologically plausible impairment not only dopamine but also serotonin biosynthesis, so it is possibly associated
with mood disorders, depression, sleep disturbances, and migraine.
DYT11: Myoclonus-Dystonia:
➢ Mutations in the epsilon sarcoglycan (SGCE) gene and onset is usually in childhood or early adolescence.
➢ The myoclonic jerks movements most often affecting the neck, trunk, and upper limbs.
➢ The disease is inherited as an autosomal dominant trait with reduced penetrance.
➢ MD patients carrying large deletions within the DYT11 locus may have associated phenotypes such as delayed
skeletal development and severe osteoporosis.
14. DYT-PRRT2: paroxysmal kinesigenic dyskinesia (DYT10)
➢ Usually starts in childhood or adolescence and is triggered by sudden movements.
➢ Attacks usually last several minutes and may appear up to 100 times per day.
➢ Missense and truncating mutations in the Proline-rich transmembrane protein 2 (PRRT2)
gene were identified as the cause of PKD
15. ➢ The TOR1A gene encodes a 332 amino acid protein, torsinA, which is a
member of the AAA+ ATPase superfamily.
➢ These proteins are Mg++-dependent ATPase activity and typically form
six-membered, homomeric ring structures.
➢ TorsinA usually located predominantly in the lumen of the endoplasmic
reticulum / nuclear envelope (NE).
➢ Torsin A is widely distributed throughout the central nervous system,
e.g. cerebral cortex, striatum, substantia nigra pars compacta,
thalamus, hippocampus, cerebellum, midbrain, pons and spinal cord
➢ Associated with a variety of functions including association with
membrane-spanning proteins, binding in the nuclear envelope, vesicle
recycling and membrane trafficking.
➢ DYT1 dystonia is an autosomal-dominant disease invariably caused by
mutation in the TOR1A gene
TorsinA gene:
Granata et. al.2010
16. ➢ LAP1, (lamina associated polypeptide 1) an inner nuclear membrane (INM) protein,
interacts with A- and B-type lamins through its N-terminal nuclear domain.
➢ LULL1 (luminal domain like LAP1) localizes to the ER and has an N-terminal domain
that projects into the cytoplasm.
➢ Torsin A are essentially inactive in isolation and strictly require the stimulation of
one of two distinctly localizing transmembrane cofactors, LAP1 (lamina associated
polypeptide 1) or LULL1 (luminal domain like LAP1)
Torsin
LAP1 or LULL
Domain organization of Tor A, TorB, LAP1 &LULL1
Mixed hexameric assembly
for Torsin and cofactors
Structural models of Torsin and cofactors:
Structural model for the composite active site at
the interface of LAP1 (orange) and TorA (green)
Brian A Sosa et. al. 2014
Torsin activation and localization
when it is bound to LAP1 or LULL1
Goodchild et. al. 2005
17. Normal nuclear envelope and
contiguous endoplasmic reticulum
Torsin (green) and LULL1 (yellow))
TEM image of blebs
seen in Torsin
deficient cells.
Mouse models and human diseases of TorA and LAP1:
➢ The unifying hallmark of Torsin or cofactor manipulation or
knockout is a ‘blebbing’ INM into the perinuclear space (PNS) of
the nuclear envelope.
➢ In TorA deficient mice, this phenotype is restricted to neuronal
tissues, but LAP1 KO model, a highly similar blebbing phenotype
was observed, including non-neuronal tissues.
➢ Mice with a conditional deletion of TorA from the central nervous
system (CNS) have an average lifespan of 10 days whereas mice
with one TorA ΔE allele and one allele with TorA selectively
deleted in the CNS (TorA Δ E/) are viable and demonstrate INM
blebbing and dystonic symptoms
➢ Mutation in LAP1 is highly associated with dystonia, muscular
dystrophy, and cardiomyopathy
Whether these LAP1-deficient phenotypes are tied with Torsins or if LAP1 has Torsin independent functions?
Goodchild et. al. 2005
18. Functional perspectives: Torsin at the nuclear envelope: (Hypothetical model)
Budding pathway through the
nuclear envelope
that may require Torsin and
LAP1
Torsin may mediate the assembly or
disassembly of a protein
complex in the NE, such as the LINC
complex
Nuclear envelope before and after NE reformation
Torsin may directly or indirectly mediate this
reformation Torsin may mediate fusion between the
inner and outer nuclear membranes during
interphase nuclear pore complex assembly
Torsin may be required for the scission reaction that is required to pinch off vesicles from the INM
VahbizJokhi 2013
VahbizJokhi 2013
RNA-protein complexes (RNPs), These RNPs are shuttled
to distinct cellular locales where, upon specific stimuli
19. Discussion:
➢ The precise biological functions of the Torsin ATPase/cofactor machinery is still unknown.
➢ But it is clear that Torsin have critical functions for NE integrity.
➢ Understanding the structure and complex stoichiometry of Torsin and cofactors will enable
us to dissect the intricate regulation of the Torsin ATPase machine.
➢ Understanding of insights into how ATPase activation is achieved and regulated in cells.
