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

Vikram Khurana, Jian Peng, Chee Yeun Chung, Pavan K. Auluck, Saranna Fanning, Daniel F. Tardiff, Theresa Bartels, Martina Koeva, Stephen W. Eichhorn, Hadar Benyamini, Yali Lou, Andy Nutter-Upham, Valeriya Baru, Yelena Freyzon, Nurcan Tuncbag, Michael Costanzo, Bryan Joseph San Luis, David C. Schöndorf, M. Inmaculada Barrasa, Sepehr EhsaniNeville Sanjana, Quan Zhong, Thomas Gasser, David P. Bartel, Marc Vidal, Michela Deleidi, Charles Boone, Ernest Fraenkel, Bonnie Berger, Susan Lindquist

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)157-170.e14
JournalCell Systems
Issue number2
StatePublished - Feb 22 2017
Externally publishedYes


  • LRRK2
  • Parkinson's disease
  • RNA-binding protein
  • VPS35
  • alpha-synuclein
  • iPS cell
  • mRNA translation
  • stem cell
  • vesicle trafficking
  • yeast

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology


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