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 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.
Ackerley
Steven
S
Departments of Neuroscience and Neurology, The Institute of Psychiatry, Kings College, London, UK.
Grierson
Andrew J
AJ
Banner
Steven
S
Perkinton
Michael S
MS
Brownlees
Janet
J
Byers
Helen L
HL
Ward
Malcolm
M
Thornhill
Paul
P
Hussain
Kader
K
Waby
Jennifer S
JS
Anderton
Brian H
BH
Cooper
Jonathan D
JD
Dingwall
Colin
C
Leigh
P Nigel
PN
Shaw
Christopher E
CE
Miller
Christopher C J
CC
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D019556:COS Cells; D004195:Disease Models, Animal; D005333:Fetus; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases
D016900:Neurofilament Proteins; C051774:neurofilament protein H; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases