Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways
| Autor: | Stephen W. Eichhorn, Neville E. Sanjana, Saranna Fanning, Sepehr Ehsani, David C. Schöndorf, Vikram Khurana, Martina Koeva, Chee Yeun Chung, M. Inmaculada Barrasa, Marc Vidal, Yali Lou, Ernest Fraenkel, Thomas Gasser, Bryan Joseph San Luis, Nurcan Tuncbag, Charles Boone, Hadar Benyamini, Theresa Bartels, Jian Peng, Bonnie Berger, Michael Costanzo, Daniel F. Tardiff, Susan Lindquist, Andy Nutter-Upham, Michela Deleidi, Pavan K. Auluck, Yelena Freyzon, Quan Zhong, Valeriya Baru, David P. Bartel |
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| Přispěvatelé: | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biological Engineering, Peng, Jian, Koeva, Martina I, Tuncbag, Nurcan, Fraenkel, Ernest |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry [Ataxin-2] chemistry [Eukaryotic Initiation Factor-4G] VPS35 chemistry.chemical_compound metabolism [Endoplasmic Reticulum] EIF4G1 protein human genetics [Amyloid beta-Peptides] metabolism [alpha-Synuclein] Induced pluripotent stem cell Ataxin-2 Genetics Parkinsonism TDP-43 protein human pathology [Neurodegenerative Diseases] Neurodegenerative Diseases cytology [Induced Pluripotent Stem Cells] LRRK2 metabolism [Eukaryotic Initiation Factor-4G] metabolism [Induced Pluripotent Stem Cells] DNA-Binding Proteins metabolism [Neurons] genetics [Gene Regulatory Networks] genetics [alpha-Synuclein] alpha-Synuclein genetics [Saccharomyces cerevisiae] Disease Susceptibility metabolism [DNA-Binding Proteins] Genome Fungal Histology metabolism [Ataxin-2] Metal ion transport metabolism [Amyloid beta-Peptides] genetics [DNA-Binding Proteins] Computational biology Biology Article Pathology and Forensic Medicine 03 medical and health sciences Gene interaction ddc:570 medicine Humans Gene Alpha-synuclein Amyloid beta-Peptides metabolism [Saccharomyces cerevisiae] Cell Biology medicine.disease nervous system diseases 030104 developmental biology chemistry genetics [Neurodegenerative Diseases] cytology [Neurons] Eukaryotic Initiation Factor-4G |
| Zdroj: | Elsevier Cell systems 4(2), 157-170.e14 (2017). doi:10.1016/j.cels.2016.12.011 |
| DOI: | 10.1016/j.cels.2016.12.011 |
| Popis: | 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: alpha-synuclein; iPS cell; Parkinson’s disease; stem cell; mRNA translation; RNA-binding protein; LRRK2; VPS35; vesicle trafficking; yeast |
| Databáze: | OpenAIRE |
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