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Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.
Khurana, Vikram; Peng, Jian; Chung, Chee Yeun; Auluck, Pavan K; Fanning, Saranna; Tardiff, Daniel F; Bartels, Theresa; Koeva, Martina; Eichhorn, Stephen W; Benyamini, Hadar; Lou, Yali; Nutter-Upham, Andy; Baru, Valeriya; Freyzon, Yelena; Tuncbag, Nurcan; Costanzo, Michael; San Luis, Bryan-Joseph; Schöndorf, David C; Barrasa, M Inmaculada; Ehsani, Sepehr; Sanjana, Neville; Zhong, Quan; Gasser, Thomas; Bartel, David P; Vidal, Marc; Deleidi, Michela; Boone, Charles; Fraenkel, Ernest; Berger, Bonnie; Lindquist, Susan.
Afiliação
  • Khurana V; 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: vkhuran
  • Peng J; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Laboratory and Department of Mathematics, MIT, Cambridge, MA 02139, USA.
  • Chung CY; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Auluck PK; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Fanning S; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Tardiff DF; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Bartels T; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Koeva M; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
  • Eichhorn SW; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Benyamini H; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Lou Y; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Nutter-Upham A; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Baru V; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Freyzon Y; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Tuncbag N; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
  • Costanzo M; Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
  • San Luis BJ; Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
  • Schöndorf DC; Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
  • Barrasa MI; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Ehsani S; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Sanjana N; 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.
  • Zhong Q; Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
  • Gasser T; Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
  • Bartel DP; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Vidal M; 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.
  • Deleidi M; Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
  • Boone C; Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada.
  • Fraenkel E; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA. Electronic address: fraenkel-admin@mit.edu.
  • Berger B; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: bab@csail.mit.edu.
  • Lindquist S; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; HHMI, Department of Biology, MIT, Cambridge, MA 02139, USA.
Cell Syst ; 4(2): 157-170.e14, 2017 02 22.
Article em En | MEDLINE | ID: mdl-28131822
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.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Doenças Neurodegenerativas / Alfa-Sinucleína Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Syst Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Doenças Neurodegenerativas / Alfa-Sinucleína Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Syst Ano de publicação: 2017 Tipo de documento: Article