ArticleCell systems2017
Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.
Article in Cell systems, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed.
- A Framework for Benchmarking Pathway Reconstruction Algorithms.bioRxiv : the preprint server for biology · 2026Article
- NERINE reveals rare variant associations in gene networks across phenotypes and implicates an SNCA-PRL-LRRK2 subnetwork in Parkinson's disease.Cell genomics · 2026Article
- High-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effects.Molecular cell · 2026Article
- Mutational Scanning of α-Synuclein using a Clickable Protein Tag Reveals Determinants of Membrane-Induced Aggregation.bioRxiv : the preprint server for biology · 2026Article
- Concentration-dependent mutational scanning probes the cellular folding landscape of α-synuclein in yeast.Protein science : a publication of the Protein Society · 2026Article
- Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α-Synuclein in Yeast.bioRxiv : the preprint server for biology · 2025Article
- From Yeast to Therapeutics: Modeling Neurodegenerative Diseases in Saccharomyces cerevisiae.Yeast (Chichester, England) · 2025Review
- Decoding the Functional Interactome of Non-Model Organisms with PHILHARMONIC.bioRxiv : the preprint server for biology · 2025Article
- Article
- Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.Molecular brain · 2024Article
- Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
- Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons.Science advances · 2024Article
- From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein.International journal of molecular sciences · 2024Review
- Tuning Hsp104 specificity to selectively detoxify α-synuclein.Molecular cell · 2023Article
- (Dys)functional insights into nucleic acids and RNA-binding proteins modulation of the prion protein and α-synuclein phase separation.Biophysical reviews · 2023Review
- Supervised biological network alignment with graph neural networks.Bioinformatics (Oxford, England) · 2023Article
- Genetics and Pathogenesis of Parkinson's Syndrome.Annual review of pathology · 2023Review
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- Network-based approaches for modeling disease regulation and progression.Computational and structural biotechnology journal · 2023Review
- Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research.International journal of molecular sciences · 2022Review
14 more citing papers are in PubMed but not listed here.
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30 authors.
Funding
Abstract
Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To "humanize" this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology. TransposeNet linked α-syn to multiple parkinsonism genes and druggable targets through perturbed protein trafficking and ER quality control as well as mRNA metabolism and translation. A calcium signaling hub linked these processes to perturbed mitochondrial quality control and function, metal ion transport, transcriptional regulation, and signal transduction. Parkinsonism gene interaction profiles spatially opposed in the network (ATP13A2/PARK9 and VPS35/PARK17) were highly distinct, and network relationships for specific genes (LRRK2/PARK8, ATXN2, and EIF4G1/PARK18) were confirmed in patient induced pluripotent stem cell (iPSC)-derived neurons. This cross-species platform connected diverse neurodegenerative genes to proteinopathy through specific mechanisms and may facilitate patient stratification for targeted therapy.
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