Tubulin neuronal microtubules

In neurons, microtubules are responsible for axonal transport and longitudinal axon growth, while neurofilaments are related to radial growth, so that axonal diameter (and thus conduction velocity) are roughly proportional to neurofilament content. Type V IFs are the lamins associated with the nuclear membrane. Actin, tubulin, and several of the intermediate filament proteins are found in all cells. 

The T-protein is represented in neurons under normal conditimis. It is involved in the incorporation of tubulin into microtubules, stabilizing them, and affecting transport in axons [14]. Intracellular NFTs, consisting of paired helical fibers of paired helical filaments, arise within the course of AD. The main component of these fibers is hyperphosphorylated x-protein [15] that disrupts the formation and structure of tubulin and induces destabilization [16]. The influence of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3p (GSK-3p) is a significant factor of hyperphosphorylation [17]. Recent... 

Janke C, Kneussel M (2010) Tubulin post-translational modifications encoding functions on the neuronal microtubule cytoskeleton. Trends Neurosci 33 362-372... 

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. 

Lewy bodies are typical in neuronal degeneration, which is accompanied by the presence of these eosinophilic intracellular inclusions of 5-25 pm diameter in a proportion of still surviving neurons. Lewy bodies contain neurofilament, tubulin, microtubule-associated proteins 1 and 2, and gelsolin, an actin-modulating protein. 

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. 

The proportion of a- and P-mbulin isoforms varies in neurons in different brain regions, and a single neuron may express a number of different tubulin isoforms. The multitubulin hypothesis suggests that microtubules composed of different mbulin isoforms have different functional roles (Sullivan, 1988). 

When tubulin heterodimers are assembled into microtubules, they form linear protofilaments with the P-tubulin subunit of one tubulin molecule linking covalently with the a-subunit of the next. Direct examination by electron microscopy of tannic acid-treated specimens has shown that micrombules in neurons and the A-microtubules of cilia and flagella have 13 protofilaments arranged side to side to form a cylinder around what appears to be an empty lumen. 

Mutant Tbce mice. Progressive motor neuropathy (PMN), an autosomal recessive murine disease, manifests as weakness beginning within a few weeks of birth [14, 136]. These mice are homozygous for a Trp 524 Gly substitution of Tbce (tubulin-specific chaperone E), localized to mouse chromosome 13 [14]. Tbce mRNA is present in neurons in the spinal cord. Degenerative changes are conspicuous in motor axons, and ultrastructural studies of peripheral nerves of PMN mice disclose reduced numbers of microtubules in these axons. Mutations of the highly conserved Trp524 residue, which appears to influence... 

Isolated microtubules always contain small amounts of larger 300-kDa microtubule-associated proteins (MAPS).330 These elongated molecules may in part lie in the grooves between the tubulin subunits and in part be extended outward to form a low-density layer around the tubule.283 309 Nerve cells that contain stable microtubules have associated stabilizing proteins.331 A family of proteins formed by differential splicing of mRNA are known as tau. The tau proteins are prominent components of the cytoskeleton of neurons. They not only interact with microtubules but also undergo reversible phosphorylation. Hyperphosphorylated tau is the primary component of the paired helical filaments found in the brains of persons with Alzheimer disease.330... 

In interphase, microtubules are stabilized by several kinds of proteins that are found all along microtubules and are called MAPs. They tend to have repeating domains, which allow each MAP molecule to associate with more than one tubulin dimer. This produces a doubly effective method of controlling assembly, in that the conformations of several tubulin dimers may be individually stabilized and the stabilized subunits are also cross-linked. The binding of these structural MAPs is in turn controlled by kinases and phosphatases (Cassimeris and Spittle, 2001). During mitosis they are phosphorylated and detach from tubulin, whose assembly and disassembly comes under the control of proteins that operate more at the ends of microtubules. Differentiated cells, such as neurons, do not divide. However, as microtubules and MAPs are slowly transported along axons (Baas and Buster, 2004), the MAPs maybe phosphorylated in particular places, at times when structural plasticity is required for making synapses or other contacts. 

Tau protein was first discovered as an acid- and heat-stable protein essential for microtubule assembly. It was identified as a factor that lowered the concentration at which tubulin polymerizes into microtubules in the brain. Tau is one such neuronal MAP, which localizes primarily in the axon with a molecular tau weight of... 

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