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

Author(s)
Khurana, Vikram; Chung, Chee Yeun; Auluck, Pavan K.; Fanning, Saranna; Tardiff, Daniel F.; Bartels, Theresa; Eichhorn, Stephen W.; Benyamini, Hadar; Lou, Yali; Nutter-Upham, Andy; Baru, Valeriya; Freyzon, Yelena; Costanzo, Michael; San Luis, Bryan-Joseph; Schöndorf, David C.; Barrasa, M. Inmaculada; Ehsani, Sepehr; Sanjana, Neville; Zhong, Quan; Gasser, Thomas; Bartel, David P.; Vidal, Marc; Deleidi, Michela; Boone, Charles; Berger, Bonnie; Lindquist, Susan; Peng, Jian; Koeva, Martina I; Tuncbag, Nurcan; Fraenkel, Ernest; ... Show more Show less
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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. Keywords: alpha-synuclein; iPS cell; Parkinson’s disease; stem cell; mRNA translation; RNA-binding protein; LRRK2; VPS35; vesicle trafficking; yeast
Date issued
2017-01
URI
http://hdl.handle.net/1721.1/115388
Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Biological Engineering
Journal
Cell Systems
Publisher
Elsevier
Citation
Khurana, Vikram et al. “Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.” Cell Systems 4, 2 (February 2017): 157–170 © 2017 The Authors
Version: Final published version
ISSN
2405-4712

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