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DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of α-synuclein toxicity and oligomerization
Blagovesta Popova1, Dan Wang1, Christina Pätz1
1Department of Molecular Microbiology and Genetics, Institute for Microbiology and Genetics, University of Goettingen, Göttingen, Germany.
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.
Insights
Researchers identified novel yeast genes that modulate alpha-synuclein toxicity, a hallmark of Parkinson's disease. Targeting the nucleolar protein DDX10, which interacts with alpha-synuclein, may offer new therapeutic strategies for Parkinson's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Parkinson's disease (PD) is characterized by alpha-synuclein protein misfolding and aggregation.
- Understanding cellular mechanisms modulating alpha-synuclein toxicity is crucial for developing PD therapies.
Purpose of the Study:
- To identify novel genetic modulators of alpha-synuclein toxicity using a yeast model.
- To investigate the role of nucleolar processes in alpha-synuclein-mediated cellular dysfunction.
Main Methods:
- Screened yeast essential gene collections for modulators of alpha-synuclein toxicity.
- Analyzed effects on gene expression, RNA processing, and protein degradation.
- Investigated protein-protein interactions between alpha-synuclein and identified modulators.
Main Results:
- Identified 98 novel modulators of alpha-synuclein toxicity, including genes involved in transcription, RNA processing, and protein degradation.
- Alpha-synuclein expression altered pre-ribosomal RNA levels in yeast and human cells.
- The nucleolar DEAD-box helicase Dbp4 (human ortholog DDX10) was a key modulator; its downregulation rescued toxicity, while overexpression caused synthetic lethality.
- Alpha-synuclein interacts with Dbp4/DDX10, sequestering it and stabilizing toxic oligomers.
Conclusions:
- Discovered a novel link between nucleolar function and alpha-synuclein toxicity in Parkinson's disease.
- DDX10 emerges as a potential therapeutic target for Parkinson's disease by modulating alpha-synuclein aggregation and toxicity.
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