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

• Published in: PLoS genetics Vol. 17; no. 3
• Main Authors: Popova, Blagovesta, Wang, Dan, Pätz, Christina, Akkermann, Dagmar, Lázaro, Diana F, Galka, Dajana, Kolog Gulko, Miriam, Bohnsack, Markus T, Möbius, Wiebke, Bohnsack, Katherine E, Outeiro, Tiago F, Braus, Gerhard H
• Format: Journal Article
• Language: English
• Published: Public Library of Science 03-03-2021
• Subjects: Control; Diagnosis; Drug therapy; Helicases; Inhibitor of apoptosis proteins; Neurotoxicity syndromes; Observations; Oligomers; Parkinson's disease; Physiological aspects; RNA; Germany
• ISSN: 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1009407

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.