p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis

Mol Cell Neurosci. 2004 Jun;26(2):354-64. doi: 10.1016/j.mcn.2004.02.009.


Neurofilament middle and heavy chains (NFM and NFH) are heavily phosphorylated on their carboxy-terminal side-arm domains in axons. The mechanisms that regulate this phosphorylation are complex. Here, we demonstrate that p38alpha, a member of the stress-activated protein kinase family, will phosphorylate NFM and NFH on their side-arm domains. Aberrant accumulations of neurofilaments containing phosphorylated NFM and NFH side-arms are a pathological feature of amyotrophic lateral sclerosis (ALS) and we also demonstrate that p38alpha and active forms of p38 family kinases are associated with these accumulations. This is the case for sporadic and familial forms of ALS and also in a transgenic mouse model of ALS caused by expression of mutant superoxide dismutase-1 (SOD1). Thus, p38 kinases may contribute to the aberrant phosphorylation of NFM and NFH side-arms in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • COS Cells
  • Disease Models, Animal
  • Fetus
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 14
  • Mitogen-Activated Protein Kinases / metabolism*
  • Motor Neurons / enzymology*
  • Motor Neurons / pathology
  • Mutation / genetics
  • Nerve Degeneration / enzymology*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / physiopathology
  • Neurofilament Proteins / metabolism*
  • Phosphorylation
  • Rats
  • Superoxide Dismutase / deficiency
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • p38 Mitogen-Activated Protein Kinases


  • Neurofilament Proteins
  • neurofilament protein H
  • Sod1 protein, mouse
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Mitogen-Activated Protein Kinase 14
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases