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

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

Author information

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

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