@article{e512d544ba9e48bb8eea9f8685206cde,
title = "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 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 = "LRRK2, Parkinson's disease, RNA-binding protein, VPS35, alpha-synuclein, iPS cell, mRNA translation, stem cell, vesicle trafficking, yeast",
author = "Vikram Khurana and Jian Peng and Chung, {Chee Yeun} and Auluck, {Pavan K.} and Saranna Fanning and Tardiff, {Daniel F.} and Theresa Bartels and Martina Koeva and Eichhorn, {Stephen W.} and Hadar Benyamini and Yali Lou and Andy Nutter-Upham and Valeriya Baru and Yelena Freyzon and Nurcan Tuncbag and Michael Costanzo and {San Luis}, {Bryan Joseph} and Sch{\"o}ndorf, {David C.} and Barrasa, {M. Inmaculada} and Sepehr Ehsani and Neville Sanjana and Quan Zhong and Thomas Gasser and Bartel, {David P.} and Marc Vidal and Michela Deleidi and Charles Boone and Ernest Fraenkel and Bonnie Berger and Susan Lindquist",
note = "Funding Information: Research was supported by an HHMI Collaborative Innovation Award (V.K., C.Y.C., and S.L.), the JPB Foundation (V.K., C.Y.C., and S.L.), an American Brain Foundation and Parkinson's Disease Foundation Clinician-Scientist Development Award (V.K.), the Multiple System Atrophy Coalition (V.K.), the NIH/NIA (grant K01 AG038546, C.Y.C.), the Eleanor Schwartz Charitable Foundation (S.L.), the NIH (grants R01 NS 089076 and U54 NS 091046, E.F.; R01GM081871, B.B.; HG006061, M.V. and S.L.; and P50HG004233 and U01HG001715, M.V.). We thank Drs. Prathapan Thiru and George Bell, Bioinformatics and Research Computing (BaRC; Whitehead Institute) for expert assistance; Kristina Fischer for important technical assistance; Drs. Luke Whitesell, Philip de Jager, Mel Feany, Aftabul Haque, David Hill, Priyanka Narayan, and Linda Clayton for stimulating discussion and critical comments on the manuscript; and Dr. Julie Valastyan for yeast strain construction. We dedicate this manuscript to Dr Susan Lindquist, our incomparable mentor and colleague, who passed away while this manuscript was in its final stages of revision. Funding Information: Research was supported by an HHMI Collaborative Innovation Award (V.K., C.Y.C., and S.L.), the JPB Foundation (V.K., C.Y.C., and S.L.), an American Brain Foundation and Parkinson{\textquoteright}s Disease Foundation Clinician-Scientist Development Award (V.K.), the Multiple System Atrophy Coalition (V.K.), the NIH/NIA (grant K01 AG038546 , C.Y.C.), the Eleanor Schwartz Charitable Foundation (S.L.), the NIH (grants R01 NS 089076 and U54 NS 091046 , E.F.; R01GM081871 , B.B.; HG006061 , M.V. and S.L.; and P50HG004233 and U01HG001715 , M.V.). We thank Drs. Prathapan Thiru and George Bell, Bioinformatics and Research Computing (BaRC; Whitehead Institute) for expert assistance; Kristina Fischer for important technical assistance; Drs. Luke Whitesell, Philip de Jager, Mel Feany, Aftabul Haque, David Hill, Priyanka Narayan, and Linda Clayton for stimulating discussion and critical comments on the manuscript; and Dr. Julie Valastyan for yeast strain construction. We dedicate this manuscript to Dr Susan Lindquist, our incomparable mentor and colleague, who passed away while this manuscript was in its final stages of revision. Publisher Copyright: {\textcopyright} 2017 The Authors",
year = "2017",
month = feb,
day = "22",
doi = "10.1016/j.cels.2016.12.011",
language = "English (US)",
volume = "4",
pages = "157--170.e14",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "2",
}