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Neurofilaments

Phosphorylation and Signal Transduction

  • Chapter
Intermediate Filaments

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Abstract

Neurofilaments belong to the Class IV family of Intermediate filaments and are neuron-specific. They are classed into three distinct groups according to their molecular masses; NF-H (heavy chain), NF-M (middle-chain) and NF-L (light chain). Together with microtubules and their associated proteins, neurofilaments make up the dynamic axonal cytoskeleton. Neurofilaments comprise a central alpha helical coil-coiled domain flanked by an amino terminal head domain and in the case of NF-H and NF-M, a hypervariable carboxy-terminal tail domain. Neurofilaments participate in dynamic properties of the axonal cytoskeleton such as axon outgrowth, axonal transport and the control of axonal caliber. They contain multiple phosphorylation sites in their amino-head and carboxy-tail domains that are phosphorylated topographically by a number of kinases and the phosphorylation of neurofilaments is related to their functions. Expression and phosphorylation of neurofilaments is developmentally regulated and most of the phosphorylation occurs in the tail domains in the mature nervous system. Kinases that have been found to phosphorylate neurofilaments include PKA, CKI, CKII CaMK and the proline directed kinases. The proline directed kinases such as Cdk5, members of the MAP kinase family (p38, SAPK and ERK1/2) and GSK3 phosphorylate the KSP repeats found in NF-M and NF-H tail domains. Aberrant hyperphosphorylation of neurofilaments in dendrites and cell bodies are seen in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer’s disease, Parkinson’s disease, Pick’s disease and Dementia with Lewy bodies. Thus, defects in compartmentalization of cytoskeletal protein phosphorylation may contribute to pathology seen in these diseases. Neurofilament phosphorylation is affected by signal transduction pathways. Calcium influx into neurons causes the phosphorylation of NF-M through the activation of the ERK1/2. Integrin mediated signaling also causes the phosphorylation of NF-H through the activation of Cdk5 activity. Recent studies have also shown that kinase cascades can be affected by myelin associated glycoprotein (MAG), a major glial protein found in periaxonal membranes of glial cells. MAG appears to be involved in bi-directional signaling affecting axonal properties such as axonal caliber, phosphorylation of neurofilaments and mediating the activity of ERK1/2 and Cdk5. Thus, signal transduction pathways are involved in the phosphorylation of the KSP repeats found in NF-M and NF-H.

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Authors and Affiliations

  1. Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, USA

    Sashi Kesavapany

  2. Laboratory of Molecular and Cellular Neurobiology National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, USA

    Richard H. Quarles

  3. Room 4D-28, Building 36, MSC 4130, NINDS, NIH, 36 Convent Drive, Bethesda, Maryland, 20892, USA

    Harish C. Pant

Authors
  1. Sashi Kesavapany
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  2. Richard H. Quarles
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  3. Harish C. Pant
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© 2006 Landes Bioscience and Springer Science+Business Media

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Kesavapany, S., Quarles, R.H., Pant, H.C. (2006). Neurofilaments. In: Intermediate Filaments. Springer, Boston, MA. https://doi.org/10.1007/0-387-33781-4_4

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