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neurofilaments

Thursday 18 March 2004

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

- Lariviere RC, Julien JP. Functions of intermediate filaments in neuronal development and disease. J Neurobiol. 2004 Jan;58(1):131-48. PMID: 14598376

- Kesavapany S, Li BS, Pant HC. Cyclin-dependent kinase 5 in neurofilament function and regulation. Neurosignals. 2003 Sep-Oct;12(4-5):252-64. PMID: 14673212

- Al-Chalabi A, Miller CC. Neurofilaments and neurological disease. Bioessays. 2003 Apr;25(4):346-55. PMID: 12655642

- Miller CC, Ackerley S, Brownlees J, Grierson AJ, Jacobsen NJ, Thornhill P. Axonal transport of neurofilaments in normal and disease states. Cell Mol Life Sci. 2002 Feb;59(2):323-30. PMID: 11924605

- Perrone Capano C, Pernas-Alonso R, di Porzio U. Neurofilament homeostasis and motoneurone degeneration. Bioessays. 2001 Jan;23(1):24-33. PMID: 11135306

- Julien JP. Neurofilament functions in health and disease. Curr Opin Neurobiol. 1999 Oct;9(5):554-60. PMID: 10508735

- Leung CL, Flores RL, Liem RK. The complexity of intermediate filaments in the nervous system. Subcell Biochem. 1998;31:497-526. PMID: 9932504

- Julien JP, Mushynski WE. Neurofilaments in health and disease. Prog Nucleic Acid Res Mol Biol. 1998;61:1-23. PMID: 9752717

- Lee MK, Cleveland DW. Neuronal intermediate filaments. Annu Rev Neurosci. 1996;19:187-217. PMID: 8833441

- Xu Z, Dong DL, Cleveland DW. Neuronal intermediate filaments: new progress on an old subject. Curr Opin Neurobiol. 1994 Oct;4(5):655-61. PMID: 7849521

- Lee MK, Cleveland DW. Neurofilament function and dysfunction: involvement in axonal growth and neuronal disease. Curr Opin Cell Biol. 1994 Feb;6(1):34-40. PMID: 7513179