Abstract
Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.
Highlights
Deficits in fast axonal transport (FAT) and abnormal activation of protein kinases are early pathogenic events in both SOD1-related and sporadic forms of ALS9–15, but whether amyotrophic lateral sclerosis (ALS)-linked Fused in Sarcoma/Translocated in Liposarcoma (FUS) affects FAT has not been evaluated
We have demonstrated the utility of isolated squid axoplasm as a powerful ex vivo system to study alterations in FAT induced by disease-related neuropathogenic proteins[10, 12, 20, 24,25,26,27], which were confirmed in mammalian disease models[12] and in human post-mortem central nervous system (CNS) tissues[10, 28, 29]
We sought to determine whether ALS-linked mutant FUS proteins affect FAT in the squid axoplasm preparation
Summary
Deficits in fast axonal transport (FAT) and abnormal activation of protein kinases are early pathogenic events in both SOD1-related and sporadic forms of ALS9–15, but whether ALS-linked FUS affects FAT has not been evaluated To address this issue, recombinant FUS proteins were perfused into isolated squid axoplasm and the effect on FAT examined. SOD1 and FUS have no known overlapping physiological functions, mutant and misfolded forms of these proteins appear to converge on a common pathogenic pathway that involves p38 MAP kinases Together these results identify p38 MAPK activation as a novel gain of toxic function of mutant FUS that results in reductions in FAT and strengthens the association between the p38 MAPK axis and neurodegeneration in ALS
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