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.
Highlights
Parkinson’s disease (PD) is a complex neurodegenerative disorder with diverse clinical features [1]
Systematic analysis of yeast genes, which are essential for growth, revealed that
Dbp4/DDX10 is an enhancer of α-synuclein toxicity and oligomerization reduced expression of central cellular proteostasis pathways, such as protein synthesis and ubiquitin-dependent protein degradation can enhance or reduce toxic effects of α-synuclein on yeast growth
Summary
Parkinson’s disease (PD) is a complex neurodegenerative disorder with diverse clinical features [1]. Neuronal loss in the substantia nigra and intracellular inclusions termed Lewy bodies (LB) are neuropathological hallmarks of PD. A major constituent of LB is the protein α-synuclein (αSyn) [2]. Misfolding and aggregation of αSyn plays a major role in PD pathogenesis [3]. ΑSyn accumulates and can form oligomeric species that can further mature into different types of aggregated species [4,5]. Accumulating evidence suggests that oligomeric or protofibrillar forms of αSyn are responsible for neurotoxicity [6,7,8], which makes αSyn a key target for therapeutic development. The precise molecular events underlying αSyn neurotoxicity and factors that trigger its aggregation and pathogenicity remain elusive
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