Microtubules axonal transport

The ability of dyneins to effect mechano-chemical coupling—i.e., motion coupled with a chemical reaction—is also vitally important inside eukaryotic cells, which, as already noted, contain microtubule networks as part of the cytoskele-ton. The mechanisms of intracellular, microtubule-based transport of organelles and vesicles were first elucidated in studies of axons, the long pro-... 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

Details of the mechanisms by which endocytosed material moves from the early to the late and lysosomal compartment are still poorly understood. However, portions of the EEs tubulovesicular structures may be actively transported along microtubules towards the perinuclear region of the cell in both neurons and non-neuronal cells. These endosomes on the move may enclose invaginated membranes and also internally bud off vesicles. For that reason, these complex structures are called multivesicular bodies (MVBs) [76]. Material returning by retrograde axonal transport to the neuronal cell body includes many MVBs [67]. The eventual fate of these structures may vary. Some MVBs may fuse with LEs or they may fuse with each... 

Dynein Motor protein mediating microtubule-based synaptic vesicle transport. May be involved in retrograde axonal transport to the cell body. 

Griffin, I. W., Fahnestock, K. E., Price, D. L. and Hoffman, P. N. Microtubule-neurofilament segregation produced by P,P - iminodipropionitrile evidence for the association of fast axonal transport with microtubules. /. Neurosci. 3 557-566,1983. 

The cytosol is the fluid compartment of the cell and contains the enzymes responsible for cellular metabolism together with free ribosomes concerned with local protein synthesis. In addition to these structures which are common to all cell types, the neuron also contains specific organelles which are unique to the nervous system. For example, the neuronal skeleton is responsible for monitoring the shape of the neuron. This is composed of several fibrous proteins that strengthen the axonal process and provide a structure for the location of specific membrane proteins. The axonal cytoskeleton has been divided into the internal cytoskeleton, which consists of microtubules linked to filaments along the length of the axon, which provides a track for the movement of vesicular material by fast axonal transport, and the cortical cytoskeleton. 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Peripheral neuropathy is seen in patients with this syndrome, which may be related to abnormal axonal transport, as a consequence of a defect in microtubules (79). Patients are susceptible to recurrent infections, especially with Staphylococcus aureus and beta-hemolytic streptococci. 

What does tau do normally Although it has been studied for many years, its exact functions are elusive. However, the role of the microtubules in axonal transport is well established. The tau isoforms may play a functional role in this process. The hyperphosphorylated tau of Alzheimer disease doesn t promote proper assembly of microtubules and may interfere with axonal transport of materials along the microtubules (see p. 1119).1214 1215 Alzheimer disease may reflect an imbalance between the phosphorylation and dephosphorylation processes. Another possible problem with tau may be slow isomerization of prolyl linkages because of a deficiency of a prolyl cis-trans isomerase (Box 9-F).1216... 

Shea, T. B. (2000). Microtubule motors, phosphorylation and axonal transport of neurofilaments. J. Neurocytol. 29, 873-887. 

The interphase organization of microtubules serves many roles, among the most important of which is the rapid transport of organelles and materials packaged in vesicles to various parts of a cell. This process was first observed directly in the giant axons of squid and was therefore named fast axonal transport. In highly elongated... 

In fast axonal transport, dynein motors serve to bring vesicles from near the end of the axon (the plus end of the microtubules) toward the cell body (the minus end of the microtubules). The distance traveled can be as much as a meter. Since dynein is a minus-end directed motor, how does it get out to the plus ends of the microtubules in the first place ... 

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