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

Cell Syst. 2017 Feb 22;4(2):157-170.e14. doi: 10.1016/j.cels.2016.12.011. Epub 2017 Jan 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Ataxin-2 / chemistry
  • Ataxin-2 / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Susceptibility
  • Endoplasmic Reticulum / metabolism
  • Eukaryotic Initiation Factor-4G / chemistry
  • Eukaryotic Initiation Factor-4G / metabolism
  • Gene Regulatory Networks / genetics
  • Genome, Fungal
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / pathology*
  • Neurons / cytology
  • Neurons / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Amyloid beta-Peptides
  • Ataxin-2
  • DNA-Binding Proteins
  • EIF4G1 protein, human
  • Eukaryotic Initiation Factor-4G
  • TDP-43 protein, human
  • alpha-Synuclein