The document discusses the role of microtubules inside cells and their clinical applications. Microtubules provide structural support, enable intracellular transport, and help separate chromosomes during cell division. They are made of tubulin and can grow or shrink. Disruptions to microtubule stability are associated with neurodegenerative diseases like Alzheimer's and Parkinson's. Maintaining the balance between stable and dynamic microtubule pools could help treat these diseases. Microtubules also interact with integrin-mediated cell adhesions and their tension may be locally controlled by microtubule assembly state.

1. CYTOSKELETON
AND
CLINICAL APPROACHES
Microtubles and Integrins associated
Dr. Dilveen D. Omer
PhD MOLECULAR MEDICINE

2. Contents
■ Basic info
■ Microtubules role inside the cell
■ Clinical approach
■ Molecular links between microtubules and integrin-
mediated adhesions

3. Cytoskeleton
■ Cytoplasm contains a
complex and dynamic
network consisting of
interlinking protein filaments
which form a structural
framework known as
CYTOSKELETON.
■ In eukaryotes, it is composed
of 3 main components,
- Microfilaments
- Microtubules
- Intermediate filaments

4. Cytoskeleton Function
■ It provides structural support to the cell.
■ functions in cell motility and regulation.
■ Often protects the cell.
■ Is very important in cell division.
■ Plays an important role in intracellular transport.
■ Engulf particles.
■ Brace themselves against pulling forces. It allows our muscles to contract.
■ Separate chromosomes during cell division.

5. Microtubules
■ Microtubules, the thickest fibers, are hollow rods about 25 microns in
diameter.
■ Microtubule fibers are made up of the globular protein, tubulin, and they grow
or shrink as more tubulin molecules are added or removed.
■ The basic unit of microtubules is dimer consisting of α- and β-tubulins
■ The Mechanical Role of Microtubules
in Tissue Remodeling

6. Microtubules Function
■ Transportation of water, ions or small molecules.
■ Cytoplasmic streaming (cyclosis).
■ Formation of fibers or asters of the mitotic or meiotic
spindle during cell division.
■ Formation of the structural units of the centrioles,
basal granules, cilia, and flagella.
■ are crucial for early developmental stages of the
neuron
■ are important throughout the life of the neuron, for it
to maintain its proper morphology, to enable axonal
and dendritic transport, and to accommodate
morphological changes such as alterations in dendritic
shape

7. Microtubules role inside the cell
ACT AS STRUCTURAL SUPPORT AND ORGANIZERS
■ They are stiff enough to resist the forces that can bend or compress the fibre
■ The distribution of microtubules through the cytoplasm of a cell determines
the shape of a cell
■ Maintain a key role in the internal organization of a cell
■ Some microtubules form stable structures of cilia and flagella, according to
the specific needs of the cell.
■ Cilia important in movement of fluids, such as mucus, across epithelial cells of
the respiratory tract. They move in a cyclic manner, taking strokes through the
fluid. Flagella are generally longer than cilia and are important in moving an
entire cell, such as sperm, through fluids.
■ Both cilia and flagella have structures dependent upon microtubules.

8. ACT AS AGENTS OF INTRACELLULAR MOTILITY
■ Involved in the movement of vesicles, proteins, organelles across the
cytoplasm through the cell
- Axonal movement: proteins such as neurotransmitters are secreted and
packed in membranous vesicles are transported through the axon which
consists of a number of microtubules and motor proteins which takes it
down the axon
- Chromosomal movements: Microtubules pull and push chromosomes in
dividing cells to enable the segregation of genetic material into newly
formed cells.
Cytoplasmic microtubules disassemble. Then, microtubules reassemble
into an organized structure called the mitotic spindle

9. ■ Because the barrier of the nuclear envelope is
gone, the microtubules can gain access to the
chromosomes. Microtubules are stabilized by this
binding and their assembly and disassembly cease
in order for them to carry out this function.
■ They align the chromosomes (at metaphase), pull
them apart (at anaphase), and move them toward
opposite poles of the cell (in telophase).
Microtubules within a mitotic spindle have
specified roles.
■ Polar microtubules push the spindle apart while
kinetochore microtubules attach to the
kinetochore structures of the duplicated
chromosomes. Astral microtubules that radiate out
from the centrosomes are believed to position the
spindle.

10. Microtubule-associated proteins
■ Intracellular trafficking of vesicles, proteins and RNAs is mediated by two
major classes of microtubule-associated motors
■ Motor proteins hydrolyze ATP to catalyze their own movement along
microtubules, while pulling their cargo along the network provided by the
microtubules
■ They can be classified into 2 types mainly : kinesins and dyneins that move
along the microtubules anthat move along microfilaments
■ The binding of ATP and its hydrolysis provides energy to them to travel cargo
attached to the motor

11. Kinesins
■ is a tetramer constructed by 2 identical heavy chains and 2 identical light
chains, has a globular head that binds ATP ,a neck a stalk and a fan shaped tail
that binds to the cargo to be transported
■ mutations in the kinesin gene leads
to neurodevelopmental disorders
through imbalanced canonical
motor activity.
■ kinesin, facilitate movement of
intracellular cargo that can include
membrane-bound organelles and
transport vesicles

12. Dyneins
■ it is a huge protein composed of two identical heavy chains and a variety of
intermediate and light chains. They are responsible for the movement of cilia
and flagella move towards the minus end of the microtubule.
■ They act as: As a force-generating agent in positioning the spindle and moving
chromosomes during mitosis
■ As a minus end–directed microtubular motor with a role in positioning the
centrosome and Golgi complex and moving organelles, vesicles, and particles
through the cytoplasm

14. Microtubules Associated Clinical
Approaches
■ Microtubules form important cytoskeletal structures that play a role in
establishing and maintaining neuronal polarity, regulating neuronal
morphology, transporting cargo, and scaffolding signaling molecules to form
signaling hubs.
■ Microtubule associated proteins, post-translational modifications of tubulin
subunits, microtubule severing enzymes, and signaling molecules are all known
to influence both stable and dynamic pools of microtubules.
■ Microtubule dynamics, the process of interconversion between stable and
dynamic pools, and the proportions of these two pools have the potential to
influence a wide variety of cellular processes.
■ Reduced microtubule stability has been observed in several neurodegenerative
diseases

15. ■ Some widely studied neurodegenerative diseases include: Alzheimer's
disease, Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic
Lateral Sclerosis (ALS)
■ Other common characteristics include:
- inflammatory responses
- increased oxidative stress
- microtubule defects
■ It is essential to recognize common underlying features that permit
degeneration of neurons to understand the most frequent mechanisms
contributing to disease progression.
■ Such an understanding can potentially lead to better therapeutic agents that
can retard progression of the most debilitating symptoms associated with
neurodegeneration.

16. ■ A characteristic feature of late onset of AD symptoms can also be attributed to
the gradual accumulation of aluminum to levels toxic enough to tip the
balance toward microtubule depolymerization and thus possibly neuron
degeneration
■ Similarly, Parkin, an E3 ubiquitin ligase linked to PD, strongly binds to α/β
Tubulin heterodimers and stabilizes microtubules.
■ Reduction in neurite length, number of neurite branches and synaptic
terminals, seen in PD patients, has been attributed to increased microtubule
depolymerization in the absence of functional Parkin

18. ■ Genetic mutations in the microtubule-severing enzyme Spastin, is most
commonly associated with hereditary spastic paraplegia (HSP). Spastin loss of
function results in local accumulation of detyrosinated microtubules and
reduced number of dynamic plus-ends along the axon shaft.
■ These mutations also results in axonal swellings which can be rescued by
treatment with microtubule-destabilizing drugs such as Nocodazole.
■ Collectively these studies demonstrate that reduced dynamics of microtubules
is also detrimental to neuronal health.

19. Microtubule-associated proteins and
their role in cancer metastasis
■ In the metastasis process, the reorganization of microtubules through their
dynamic properties occurs to support morphological changes associated
with cell movement
■ Besides the direct functions of microtubules, they also serve as tracking
trails for the translocation of metastasis-related signaling molecules to the
leading and/or rear edges of cells
■ several MAPs reportedly show differential expression in cancer cells
compared to that in normal cells, they likely contribute to cell migration
and invasion.

21. Molecular links between microtubules
and integrin-mediated adhesions
■ microtubules normally counteract cell contractility, and thus microtubule
disruption strongly increases the tension exerted by the actin cytoskeleton on
the cell–ECM focal adhesions
■ More specifically, one may regard focal adhesions as tension-sensing devices,
which convert cell contraction into protein modification events, such as
tyrosine phosphorylation
■ A possible mechanism of this control may be a microtubule-mediated
suppression of contractility.
■ The tension at focal adhesions developed by the actin system may affect
adhesion-dependent signaling.
■ This tension might be locally controlled by the state of microtubule assembly.

22. Refrences
■ https://www.frontiersin.org/articles/10.3389/fphar.2022.935493/full
■ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563776/
■ https://www.sciencedirect.com/science/article/pii/S0960982202707148
■ Lippincott’s Illustrated Reviews: Cell and Molecular Biology
■ https://www.frontiersin.org/articles/10.3389/fphar.2022.935493/full