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

• 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
• ISSN: 1044-7431

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.