DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of [alpha]-synuclein toxicity and oligomerization

Parkinson's disease is a neurodegenerative disorder associated with misfolding and aggregation of [alpha]-synuclein as a hallmark protein. Two yeast strain collections comprising conditional alleles of essential genes were screened for the ability of each allele to reduce or improve yeast growth upon [alpha]-synuclein expression. The resulting 98 novel modulators of [alpha]-synuclein toxicity clustered in several major categories including transcription, rRNA processing and ribosome biogenesis, RNA metabolism and protein degradation. Furthermore, expression of [alpha]-synuclein caused alterations in pre-rRNA transcript levels in yeast and in human cells. We identified the nucleolar DEAD-box helicase Dbp4 as a prominent modulator of [alpha]-synuclein toxicity. Downregulation of DBP4 rescued cells from [alpha]-synuclein toxicity, whereas overexpression led to a synthetic lethal phenotype. We discovered that [alpha]-synuclein interacts with Dbp4 or its human ortholog DDX10, sequesters the protein outside the nucleolus in yeast and in human cells, and stabilizes a fraction of [alpha]-synuclein oligomeric species. These findings provide a novel link between nucleolar processes and [alpha]-synuclein mediated toxicity with DDX10 emerging as a promising drug target.