ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in the Fused in Sarcoma (FUS) gene.
• Mutant FUS is thought to exert a toxic gain-of-function in motor neurons, but the underlying mechanisms are unclear.
• Fast axonal transport (FAT) is crucial for motor neuron maintenance and is progressively degenerated in ALS.

Purpose of the Study:

• To investigate the impact of wild-type FUS (FUS WT) and ALS-linked FUS variants on fast axonal transport (FAT).
• To elucidate the molecular mechanisms, including the p38 MAPK pathway, involved in mutant FUS-induced neurotoxicity.

Main Methods:

• Studied the effects of FUS WT and three ALS-linked FUS variants (G230C, R521G, R495X) on FAT in squid axoplasm.
• Assessed the role of the molecular chaperone Hsp110 in mitigating mutant FUS toxicity.
• Investigated the involvement of the p38 MAPK pathway in squid axoplasm and mammalian primary motor neurons.
• Analyzed p38 MAPK activation in post-mortem human ALS-FUS brain tissues.

Main Results:

• All ALS-FUS variants, but not FUS WT, impaired both anterograde and retrograde FAT in squid axoplasm.
• The molecular chaperone Hsp110 attenuated the toxic effects of mutant FUS on FAT.
• Mutant FUS impaired FAT and axonal outgrowth via aberrant activation of the p38 MAPK pathway.
• Elevated levels of active p38 MAPK were observed in human ALS-FUS brain samples.

Conclusions:

• ALS-linked FUS mutations impair fast axonal transport through a toxic gain-of-function mechanism.
• Aberrant activation of the p38 MAPK pathway is a key mediator of mutant FUS-induced neurotoxicity in ALS.
• These findings highlight a novel molecular pathway implicated in familial ALS pathogenesis.