[CRBS Seminar] Lipid metabolism alterations in FUS-linked amyotrophic lateral sclerosis (ALS)

Abstract:

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of the adult motor system, for which effective treatments remain elusive. Mutations leading to the mislocalization of FUS, an essential RNA-binding protein, have been linked to the most severe form of ALS. Despite intense research efforts, the cascade of pathological events triggering the progressive degeneration of motor neurons remains incompletely understood. Our prior investigations revealed significant lipid metabolism alterations in the spinal cord of a FUS mouse model, as well as in motor neurons derived from ALS patients induced pluripotent stem cells (iPSCs). Recent evidence suggests that dysfunctional glial cells, including oligodendrocytes, contribute to neurodegeneration in FUS-linked ALS through non-cell autonomous mechanisms. In our latest research, we investigated the impact of FUS mutations in oligodendrocyte progenitor cells (OPCs) derived from human iPSCs. Confirming the cytoplasmic mislocalization of FUS in OPCs, we uncovered significant alterations in lipid metabolism, accompanied by transcriptomic alterations related to myelin formation. Additionally, we observed mitochondria-associated ER membrane abnormalities, ER stress, and mitochondrial dysfunctions. These recent findings emphasize the pathological role of FUS in oligodendrocytes, shedding light on the intricate cellular mechanisms contributing to FUS-linked ALS pathology.