Vivo-Morpholinos: Same oligos, from cultures to critters -


Identifying candidate ALS-associated genes in yeast

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.

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