The tip of an iceberg in the Arctic Ocean near Norway, representing current knowledge about proteins involved in ALS. Image courtesy of Stanley H. Gitler, CPA.
Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease) is a severely debilitating and fatal neurodegenerative disorder. The causes are largely unknown, and only ∼10% of cases are due to familial genetic mutations. Some ALS-associated genes encode RNA-binding proteins and are prone to forming cytotoxic protein aggregates that contribute to pathology. To identify new disease-associated genes, Couthouis et al. designed a screen in yeast: they expressed 133 human proteins containing RNA-recognition motifs, and screened for those that caused cytoplasmic aggregates and reduced cell viability. Further analyses led to the identification of TAF15 as a candidate. Sequencing analysis revealed TAF15 missense mutations in several individuals with ALS, but not in healthy controls. Similar to the previously identified ALS-associated proteins FUS and TDP-43, disease-associated forms of TAF15 were shown to aggregate in cultures of primary spinal cord neurons and to cause neuro-degeneration when expressed in Drosophila. These data indicate that FUS and TDP-43 might be just the tip of the iceberg with respect to the involvement of RNA-binding proteins in ALS. In addition, this study highlights the power of yeast functional screens to identify new disease-gene candidates.
