TY - JOUR
T1 - p38α stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis
AU - Ackerley, Steven
AU - Grierson, Andrew J.
AU - Banner, Steven
AU - Perkinton, Michael S.
AU - Brownlees, Janet
AU - Byers, Helen L.
AU - Ward, Malcolm
AU - Thornhill, Paul
AU - Hussain, Kader
AU - Waby, Jennifer S.
AU - Anderton, Brian H.
AU - Cooper, Jonathan D.
AU - Dingwall, Colin
AU - Leigh, P. Nigel
AU - Shaw, Christopher E.
AU - Miller, Christopher C.J.
N1 - Funding Information:
This work was supported by grants from the Medical Research Council, The Wellcome Trust and UK Motor Neurone Disease Association including the Jim Tew Memorial Studentship and National Lotteries. We thank Roger Davis (Worcester, MA) for supplying MKK3 and MKK6 DNAs, Ron Liem (Columbia, New York) for neurofilament DNAs, Brent Zanke (Toronto, Ontario) for p38 DNA and Virginia Lee (Philadelphia, PA) for antibodies to NFM.
PY - 2004/6
Y1 - 2004/6
N2 - 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 p38α, 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 p38α 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.
AB - 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 p38α, 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 p38α 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.
UR - http://www.scopus.com/inward/record.url?scp=4644362726&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2004.02.009
DO - 10.1016/j.mcn.2004.02.009
M3 - Article
C2 - 15207859
AN - SCOPUS:4644362726
SN - 1044-7431
VL - 26
SP - 354
EP - 364
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 2
ER -