neurofilaments

Neurofilaments are neuron-specific intermediate filaments. Neurofilaments (NFs) are the most abundant structural components in large-diameter myelinated axons.

Assembled as obligate heteropolymers requiring NF-L and substoichiometric amounts of NF-M and/or NF-H, NF investment into axons is essential for establishment of axonal caliber, itself a key determinant of conduction velocity.

Use of transgenic mice to increase axonal accumulation of NFs or to express mutant NFs subunits has proven that aberrant organization or assembly of NFs is sufficient to cause disease arising from selective dysfunction and degeneration of motor neurons.

Because aberrant accumulation of NFs is a common pathology in a series of motor neuron diseases-including amyotrophic lateral sclerosis-NF misaccumulation, and the resultant disruption in axonal transport, is probably a key intermediate in the pathogenesis of these diseases.

Five major types of intermediate filament proteins are expressed in mature neurons: the three neurofilament proteins (NF-L, NF-M, and NF-H), alpha-internexin, and peripherin.

Neurofilament proteins are classed into three groups according to their molecular masses: neurofilament heavy, middle and light chains (NEFH, NEFM or NEF3, NEFL).

Neurofilaments are composed of 3 neuron-specific proteins with apparent molecular masses of 68 kD (NEFL), 125 kD (NEFM or NEF3), and 200 kD (NEFH) on SDS-gel electrophoresis. Neurofilaments assemble and form through the association of their central alpha-helical coiled-coil rod domains.

NEFH and NEF3 (NEFM) are distinct from NEFL as they contain a carboxyl-terminal tail domain, which appears to form connections with adjacent structures and other neurofilaments. Together with other axonal components such as microtubules, they form the dynamic axonal cytoskeleton.

They maintain and regulate neuronal cytoskeletal plasticity through the regulation of neurite outgrowth, axonal caliber and axonal transport.

Neurofilaments contain KSP repeats that are consensus motifs for the proline-directed kinases and are extensively phosphorylated in vivo, and their functions are thought to be regulated through their phosphorylation.

Pathology (neurofilamentopathies)

 NEFL germline mutations in

• autosomal dominant Charcot-Marie-Tooth disease of the 2E axonal form (CMT2E) (MIM.607684)
• germline mutations in Charcot-Marie-Tooth disease of the 1F type (CMT1F) (MIM.607734)

 NEFH variants in susceptibility to amyotrophic lateral sclerosis (ALS) (MIM.105400)

Animations

 Axonal transport: A movie from J Cell Biol

References

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