Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways
Name
1-s2.0-S2405471216304458-main.pdf
Size
6.48 MB
Format
Adobe PDF
Checksum (MD5)
a8295bd5a830adb0c8e5012165722cd6
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
Date Issued
January 2017
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
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
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CELS.2016.12.011
