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

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

Parkinson's disease is a neurodegenerative disorder associated with misfolding and aggregation of α-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 α-synuclein expression. The resulting 98 novel modulators of α-synuclein toxicity clustered in several major categories including transcription, rRNA processing and ribosome biogenesis, RNA metabolism and protein degradation. Furthermore, expression of α-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 α-synuclein toxicity. Downregulation of DBP4 rescued cells from α-synuclein toxicity, whereas overexpression led to a synthetic lethal phenotype. We discovered that α-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 α-synuclein oligomeric species. These findings provide a novel link between nucleolar processes and α-synuclein mediated toxicity with DDX10 emerging as a promising drug target.

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Author(s): Popova B, Wang D, Patz C, Akkermann D, Lazaro DF, Galka D, Kolog Gulko M, Bohnsack MT, Mobius W, Bohnsack KE, Outeiro TF, Braus GH

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2021

Volume: 17

Issue: 3

Online publication date: 03/03/2021

Acceptance date: 09/02/2021

Date deposited: 07/04/2021

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pgen.1009407

DOI: 10.1371/journal.pgen.1009407

PubMed id: 33657088

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