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

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 phosphor...

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Bibliographic Details
Published in:Molecular and cellular neuroscience 2004-06, Vol.26 (2), p.354-364
Main Authors: Ackerley, Steven, Grierson, Andrew J, Banner, Steven, Perkinton, Michael S, Brownlees, Janet, Byers, Helen L, Ward, Malcolm, Thornhill, Paul, Hussain, Kader, Waby, Jennifer S, Anderton, Brian H, Cooper, Jonathan D, Dingwall, Colin, Leigh, P Nigel, Shaw, Christopher E, Miller, Christopher C J
Format: Article
Language:English
Subjects:
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
p38 Mitogen-Activated Protein Kinases
Phosphorylation
Rats
Superoxide Dismutase - deficiency
Superoxide Dismutase - genetics
Superoxide Dismutase-1
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Summary: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.
ISSN:1044-7431