Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways

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/ER quality control and mRNA metabolism/translation. A calcium signaling hub linked these processes to perturbed mitochondrial quality control/function, metal ion transport, transcriptional regulation and signal transduction. Parkinsonism gene interaction profiles spatially opposed in the network (ATP13A2/PARK9, VPS35/PARK17) were highly distinct, and network relationships for specific genes (LRRK2/PARK8, ATXN2 and EIF4G1/PARK18) were confirmed in patient iPS cell-derived neurons. This cross-species platform connected diverse neurodegenerative genes to proteinopathy through specific mechanisms, and may facilitate patient stratification for targeted therapy.

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…In addition to the many terms related to fatty acid metabolism, gene ontology analysis also revealed other enriched terms, including myofibril assembly, muscle α-actinin binding, and sperm flagellum. The component transcripts responsible for these terms being enriched are cytoskeletal genes (Figure 8b, Table 6), which is of interest given our work (Ordonez et al, 2018) as well as the work of others Esposito, Dohm, Kermer, Bähr, & Wouters, 2007;Khurana et al, 2017;Sousa et al, 2009) implicating dysfunction of the actin cytoskeleton in α-synuclein neurotoxicity. Similar to the fatty acid metabolism-related genes, the cytoskeletal genes were also downregulated in Neuron:Control (Figure 8b), though none reached statistical significance in that condition.…”

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity

“…Although these technologies provide powerful strategies for perturbing individual genes, they may not be suitable for global or combinatorial perturbation of transcriptional networks. Many complex diseases, as well as treatments required to counteract those conditions, may involve simultaneous or dynamic changes in the expression levels of many genes, which are not accessible by screens that target genes one at a time (Khurana et al, 2017; Yeger-Lotem et al, 2009). …”

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

“…This protein homeostasis system is comprised of a variety of components, including molecular chaperones, the proteolytic, ubiquitin-proteasome and autophagic degradation pathways, cellular trafficking, and other elements of the cellular stress response (3)(4)(5)(6)(21)(22)(23)(24)(25)(26). The progressive decline of the efficacy of these regulatory processes upon aging is likely to contribute to the increased susceptibility of the elderly population to ageassociated neurodegenerative disorders (3)(4)(5)(6)(21)(22)(23)(24)(25)(26)(27)(28).…”