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.
authors.affiliation: 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.
authors.forename: Vikram
authors.initials: V
authors.lastname: Khurana
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Laboratory and Department of Mathematics, MIT, Cambridge, MA 02139, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Chee Yeun
authors.initials: CY
authors.lastname: Chung
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Auluck
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Saranna
authors.initials: S
authors.lastname: Fanning
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Tardiff
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Bartels
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Koeva
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Eichhorn
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Hadar
authors.initials: H
authors.lastname: Benyamini
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Nutter-Upham
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Baru
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Freyzon
authors.affiliation: Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
authors.forename: Nurcan
authors.initials: N
authors.lastname: Tuncbag
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
authors.forename: Bryan-Joseph
authors.initials: BJ
authors.lastname: San Luis
authors.affiliation: Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: David C
authors.initials: DC
authors.lastname: Schöndorf
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: M Inmaculada
authors.initials: MI
authors.lastname: Barrasa
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Sepehr
authors.initials: S
authors.lastname: Ehsani
authors.affiliation: 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.
authors.forename: Neville
authors.initials: N
authors.lastname: Sanjana
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Bartel
authors.affiliation: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: Michela
authors.initials: M
authors.lastname: Deleidi
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.affiliation: Department of Biological Engineering, MIT, Cambridge, MA 02139, USA. Electronic address: fraenkel-admin@mit.edu.
authors.forename: Ernest
authors.initials: E
authors.lastname: Fraenkel
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: bab@csail.mit.edu.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Berger
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; HHMI, Department of Biology, MIT, Cambridge, MA 02139, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000067698:Ataxin-2 / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D004721:Endoplasmic Reticulum / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000235:genetics; D016681:Genome, Fungal; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000067698:Ataxin-2; D004268:DNA-Binding Proteins; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; C000598624:TARDBP protein, human; D051844:alpha-Synuclein
keywords: LRRK2; Parkinson’s disease; RNA-binding protein; VPS35; alpha-synuclein; iPS cell; mRNA translation; stem cell; vesicle trafficking; yeast