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 Ehsani; Neville Sanjana; Quan Zhong; Thomas Gasser; David P Bartel; Marc Vidal; Michela Deleidi; Charles Boone; Ernest Fraenkel; Bonnie Berger; Susan Lindquist

doi:10.1016/j.cels.2016.12.011

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.

Authors

Vikram Khurana¹, Jian Peng², Chee Yeun Chung³, Pavan K Auluck³, Saranna Fanning³, Daniel F Tardiff³, Theresa Bartels³, Martina Koeva⁴, Stephen W Eichhorn³, Hadar Benyamini³, Yali Lou³, Andy Nutter-Upham³, Valeriya Baru³, Yelena Freyzon³, Nurcan Tuncbag⁵, Michael Costanzo⁶, Bryan-Joseph San Luis⁶, David C Schöndorf⁷, M Inmaculada Barrasa³, Sepehr Ehsani³, Neville Sanjana⁸, Quan Zhong⁹, Thomas Gasser⁷, David P Bartel³, Marc Vidal¹⁰, Michela Deleidi⁷, Charles Boone⁶, Ernest Fraenkel¹¹, Bonnie Berger¹², Susan Lindquist¹³

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: vkhurana@bwh.harvard.edu.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Laboratory and Department of Mathematics, MIT, Cambridge, MA 02139, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
⁵ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
⁶ Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
⁷ Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; New York Genome Center and Department of Biology, New York University, New York, NY 10013, USA.
⁹ Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
¹⁰ Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA. Electronic address: fraenkel-admin@mit.edu.
¹² Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: bab@csail.mit.edu.
¹³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; HHMI, Department of Biology, MIT, Cambridge, MA 02139, USA.

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
TARDBP protein, human
alpha-Synuclein

Abstract

Publication types

MeSH terms

Substances

Grants and funding