Neurofilaments

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

Multiple sclerosis The 150-kDa calpain specific degradation product of a-spectrin increases 50% in human MS plaques.44 Degradation of the 68-kDa neurofilament protein is inhibited by a synthetic calpain inhibitor45... 

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. 

Figure 3. Electron micrographs of myelinated axons of Xenopus laevis. Upper figure Cross section of axon showing microtubules in groups in association with membrane-bound organelles. Lower figure Longitudinal section of axon showing neurofilaments and microtubules in close proximity to membrane-bound organelles. (Courtesy of Dr. R. Smith.)...

Two major types of muscle fibers are found in humans white (anaerobic) and red (aerobic). The former are particularly used in sprints and the latter in prolonged aerobic exercise. During a sprint, muscle uses creatine phosphate and glycolysis as energy sources in the marathon, oxidation of fatty acids is of major importance during the later phases. Nonmuscle cells perform various types of mechanical work carried out by the structures constituting the cytoskeleton. These strucmres include actin filaments (microfilaments), micrombules (composed primarily of a- mbulin and p-mbulin), and intermediate filaments. The latter include keratins, vimentin-like proteins, neurofilaments, and lamins. 

Takahashi S., Iwanaga T Takahashi Y., Nakano Y., et al. (1984). Neuron-specific enolase, neurofilament protein and S-100 protein protein in the olfactory mucosa of human fetuses an immunohistochemical study. Cell Tiss Res 238, 231-234. 

Lou Gehrig s disease (amyotrophic lateral sclerosis ALS) displays motor neuron deposits of hyperphosphorylated neurofilament subunits in the sporadic disease. Familial ALS, some 20% of all cases of ALS, involves dominant superoxide dismutase SOD1 mutants that can form (3-barrel aggregates [49-51]. 

Chou SM, Wang HS, Taniguchi A. Role of SOD-1 and nitric oxide/cyclic GMP cascade on neurofilament aggregation in ALS/MND. J Neurol Sci 1996 139 suppl 16-26. 

Trivedi, N., Jung, P., and Brown, A. (2007) Neurofilaments switch between distinct mobile and stationary states during their transport along axons./. Neurosci. 27, 507-516. 

Neurofilaments belong to the family of intermediate filaments and usually are found in association with neurotubules. The function of these two organelles has been... 

FIGURE 1-8 A dendrite (D) emerging from a motor neuron in the anterior horn of a rat spinal cord is contacted by four axonal terminals terminal 1 contains clear, spherical synaptic vesicles terminals 2 and 3 contain both clear, spherical and dense-core vesicles (arrow) and terminal 4 contains many clear, flattened (inhibitory) synaptic vesicles. Note also the synaptic thickenings and, within the dendrite, the mitochondria, neurofilaments and neurotubules. x33,000. 

FIGURE 1-14 Transverse sections of a myelinated axon (left) and the process of a fibrous astrocyte (right) in dog spinal cord. The axon contains scattered neurotubules and loosely packed neurofilaments interconnected by side-arm material. The astrocytic process contains a bundle of closely packed filaments with no cross-bridges, flanked by several microtubules. Sometimes, a lumen can be seen within a filament. X60,000. 

FIGURE 4-7 A typical CNS myelinated fiber from the spinal cord of an adult dog. Contrast this figure with the PNS fiber in Figure 4-4. The course of the flattened oligodendrocytic process, beginning at the outer tongue (arrow), can be traced. Note that the fiber lacks investing cell cytoplasm and a basal lamina-as is the case in the PNS. The major dense line and the paler, double intraperiod line of the myelin sheath can be discerned. The axon contains microtubules and neurofilaments. 

Myelin affects axonal structure. The presence of a myelin sheath affects the structure of the axon that it surrounds [5], presumably optimizing its properties for transmission of action potentials by saltatory conduction. Generally, one of the effects of myelin is to increase axonal diameter by inducing biochemical changes in components of the axonal cytoskeleton such as neurofilaments (see Ch. 8). The effects of myelin on axonal structure imply... 

Other diseases with disruptions in neurofilament organization include diabetic neuropathy and Charcot-Marie-Tooth disease. For these diseases, the disruption of neuro filaments may be a secondary effect as in the case of trembler axons or a direct effect. For example, some forms of Charcot-Marie-Tooth peripheral neuropathy result from mutations in a neurofilament subunit [22, 43]. In most cases, neuronal degeneration is an eventual consequence, but neuronal function may be impaired prior to substantial loss of neurons. Generally, disruptions of neurofilaments have the most severe consequences in large motor neurons, which is consistent with the fact that the largest neurons have the highest levels of neurofilament expression. 

De Waegh, S. M., Lee, V. M.-Y. and Brady, S. T. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 68 451-463,1992. 

Brownlees, J., Ackerley, S., Grierson, A. J. et al. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum. Molec. Genet. 11 2837-2844, 2002. 

Synaptobrevins (VAMPs) Synaptogyrin Synaptophysins PKA but diverge C-terminally. Synapsins Ia/b contain C-terminal phosphorylation sites for CaMKII and CDK 5. Interact with microfilaments, neurofilaments, microtubules, SH3 domains, calmodulin and annexin VI in vitro. Small-membrane proteins that are cleaved by tetanus toxin and by botulinum toxins B, D, F and G. Polytopic membrane protein that is tyrosine-phosphorylated. Function unknown. Polytopic membrane proteins, including synaptoporin, that are tyrosine-phosphorylated and bind to synaptobrevins. May regulate SNARE function... 

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