Proteins axonal transport

MTs extend from the centrosome throughout the cytoplasm to the plasma membrane, where they are stabilized by caps. Sliding along the MTs, kinesin and dynein motors transport their cargoes between the center and the periphery of the cell. MTs present in the axons of neur ons are extended not only by addition of heterodimers to the plus ends but also by use of short MTs that initiate in the centrosome. Their axonal transport is mediated by dynein motors that are passively moved along actin filaments. Once formed in the axon, MTs serve as tracks for the fast axonal transport, i.e. the movement of membranous organelles and membrane proteins to the nerve ending. 

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. 

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

The receptor for NGF is TrkA, a 140 kDa cell surface protein that specifically binds NGF, but not other neurotrophins [5, 6, 9]. TrkA is expressed on the neuronal cell body and on neuronal processes. In its action as a target-derived trophic factor, NGF is secreted within the target organ and it then binds to TrkA receptors present on the growing neuronal process or synapse. The NGF-TrkA complex is then internalized and subsequently translocated to the cell body by retrograde axonal transport. In those cells that respond to NGF through autocrine or paracrine mechanisms, the growth factor can bind to any of the widely distributed TrkA molecules on the neuronal membrane. 

Fast and slow components of axonal transport differ in both their constituents and their rates. Fast transport is bidirectional many proteins that are distributed by fast... 

When labeled polypeptides traveling down the axon are analyzed by SDS polyacrylamide gel electrophoresis, materials traveling in the axon can be grouped into five distinct rate components [6], Each rate component is characterized by a unique set of polypeptides moving coherently down the axon (Fig. 28-3). As specific polypeptides associated with each rate class were identified, most were seen to move only within a single rate component. Moreover, proteins that have common functions or interact with each other tend to be moved together. These observations led to a new view of axonal transport, the structural hypothesis [7]. This model can be stated simply proteins and other molecules move down the axon as component parts of discrete subcellular structures rather than as individual molecules (Table 28-1). 

The structural hypothesis, which was formulated in response to observations that axonal transport rate components move as discrete waves, each with a characteristic rate and a distinctive composition, can explain the coherent transport of functionally related proteins and is consistent with the relatively small numbers of motor molecules in neurons. The only assumption is that the number of elements that can interact with transport motor complexes is limited, and this requires appropriate packaging of the transported material. Different rate components result from packaging of transported material into different, cytologically identifiable, structures. In fact, the faster rates reflect the transport of proteins preassembled as membranous organelles, including vesicles and... 

Drug studies demonstrated a requirement that most proteins destined for fast axonal transport traverse the Golgi stacks, where membrane proteins are post-transla-tionally modified, sorted and packaged [9] (Fig. 28-7). This suggests that proteins in fast axonal transport must either pass through the Golgi complex or associate with... 

Finally, this section has focused almost entirely on axonal transport, but dendritic transport also occurs [25]. Since dendrites usually include postsynaptic regions while most axons terminate in presynaptic elements, the dendritic and axonal transport each receive a number of unique proteins. An added level of complexity for intraneuronal transport phenomena is the intriguing observation that mRNA is routed into dendrites where it is implicated in local protein synthesis at postsynaptic sites, but ribosomal components and mRNA are largely excluded from axonal domains [26]. Regulation of protein synthesis in dendritic compartments is an important mechanism is synaptic plasticity [27,28]. The importance of dendritic mRNA transport and local protein synthesis is underscored by the demonstration that the mutation associated with Fragile X syndrome affects a protein important for transport and localization of mRNA in dendrites [27, 29], Similar processes of mRNA transport have been described in glial cells [30]. 

Although these two rate components can be identified in all nerves examined to date, the rates and the precise compositions varies among nerve populations. For example, SCa and SCb are readily resolved as discrete waves moving down optic axons, but differences in rate are smaller in the motor axons of sciatic nerve so the two peaks overlap. Moreover, virtually all tubulin moves as a single peak in SCa in optic axons, but significant amounts of tubulin move at both SCa and SCb rates in sciatic motor axons [32]. In each nerve, certain polypeptides may be used to define the kinetics for a given slow component of axonal transport. For SCa, those signature polypeptides are the NF triplet proteins, while actin, clathrin and calmodulin serve a similar role for SCb. 

Hammerschlag, R., Stone, G. C., Bolen, F. A., Lindsey, J. D. and Ellisman, M. H. Evidence that all newly synthesized proteins destined for fast axonal transport pass through the Golgi apparatus. J. Cell Biol. 93 568-575,1982. 

Smith, R. S. and Snyder, R. E. Reversal of rapid axonal transport at a lesion leupeptin inhibits reversed protein transport, but does not inhibit reversed organelle transport. Brain Res. 552 215-227,1991. 

Oblinger, M. M., Brady, S. T., McQuarrie, I. G. and Lasek, R. Differences in the protein composition of the axonally transported cytoskeleton in peripheral and central mammalian neurons. /. Neurosci. 7 453-462,1987. 

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