Yeast genetic screen reveals novel therapeutic strategy for ALS

摘要

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by a selective loss of motor neurons. There is no cure and few effective treatments. The RNA-binding protein TDP-43 contributes to the pathogenesis of ALS. TDP-43 is depleted from the nucleus and accumulates in cytoplasmic aggregates in the degenerating neurons and glia of most ALS patients. Furthermore, mutations in the TDP-43 gene cause rare familial and sporadic forms of the disease. Thus, therapeutic strategies targeting TDP-43 may be efficacious. We have used the yeast model system to identify the mechanisms by which TDP-43 aggregation contributes to ALS and to identify approaches to protect cells from the toxic effects of TDP-43 aggregation. Using an unbiased yeast genetic screen we discovered Dbr1 as a potent suppressor of TDP-43 toxicity. Yeast cells in which Dbr1 is deleted are resistant to TDP-43 toxicity. Dbr1 inhibition in mammalian cells is also sufficient to protect against TDP-43 cytotoxicity. Here, we review this recent discovery, highlighting future approaches aimed at extending these studies and pursuing Dbr1 as a novel therapeutic target for ALS.