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

被引：75

作者：

Khurana, Vikram ^{[1
,2
,3
,4
]}

Peng, Jian ^{[1
,5
,6
,19
]}

Chung, Chee Yeun ^{[1
,20
]}

Auluck, Pavan K. ^{[1
]}

Fanning, Saranna ^{[1
]}

Tardiff, Daniel F. ^{[1
,20
]}

Bartels, Theresa ^{[1
]}

Koeva, Martina ^{[1
,7
]}

Eichhorn, Stephen W. ^{[1
]}

Benyamini, Hadar ^{[1
]}

Lou, Yali ^{[1
]}

Nutter-Upham, Andy ^{[1
]}

Baru, Valeriya ^{[1
]}

Freyzon, Yelena ^{[1
]}

Tuncbag, Nurcan ^{[7
]}

Costanzo, Michael ^{[8
]}

San Luis, Bryan-Joseph ^{[8
]}

Schoendorf, David C. ^{[9
,10
]}

Barrasa, M. Inmaculada ^{[1
]}

Ehsani, Sepehr ^{[1
]}

Sanjana, Neville ^{[11
,12
,13
]}

Zhong, Quan ^{[14
]}

Gasser, Thomas ^{[9
,10
]}

Bartel, David P. ^{[1
]}

Vidal, Marc ^{[15
,16
,17
]}

Deleidi, Michela ^{[9
,10
]}

Boone, Charles ^{[8
]}

Fraenkel, Ernest ^{[7
]}

Berger, Bonnie ^{[4
]}

Lindquist, Susan ^{[1
,18
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] Brigham & Womens Hosp, Dept Neurol, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA

[6] MIT, Dept Math, Cambridge, MA 02139 USA

[7] MIT, Dept Biol Engn, Cambridge, MA 02139 USA

[8] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada

[9] Univ Tubingen, Dept Neurodegenerat Dis, German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany

[10] Univ Tubingen, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany

[11] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[12] NYU, New York Genome Ctr, New York, NY 10013 USA

[13] NYU, Dept Biol, New York, NY 10013 USA

[14] Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA

[15] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA

[16] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[17] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[18] MIT, Dept Biol, HHMI, Cambridge, MA 02139 USA

[19] Univ Illinois, Dept Comp Sci, Urbana, IL 61801 USA

[20] Yuman Therapeut, Cambridge, MA 02139 USA

来源：

CELL SYSTEMS | 2017年 / 4卷 / 02期

关键词：

PROTEIN-INTERACTION NETWORKS; FAMILIAL PARKINSON DISEASE; INTACT YEAST-CELLS; SACCHAROMYCES-CEREVISIAE; ALZHEIMERS-DISEASE; RETROMER COMPLEX; HUMAN ES; NEURONS; MUTATIONS; RISK;

D O I：

10.1016/j.cels.2016.12.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (alpha-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact alpha-syn toxicity. To "humanize'' this molecular network, we developed a computational method, Transpose Net. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology. TransposeNet linked a-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.

引用

页码：157 / +

页数：28

共 94 条

[1] Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [J].

Altschul, SF ;

Madden, TL ;

Schaffer, AA ;

Zhang, JH ;

Zhang, Z ;

Miller, W ;

Lipman, DJ .

NUCLEIC ACIDS RESEARCH, 1997, 25 (17) :3389-3402

[2] BASIC LOCAL ALIGNMENT SEARCH TOOL [J].

ALTSCHUL, SF ;

GISH, W ;

MILLER, W ;

MYERS, EW ;

LIPMAN, DJ .

JOURNAL OF MOLECULAR BIOLOGY, 1990, 215 (03) :403-410

[3]

[Anonymous], NEUROBIOLOGY AGING

[4] Gene Ontology: tool for the unification of biology [J].

Ashburner, M ;

Ball, CA ;

Blake, JA ;

Botstein, D ;

Butler, H ;

Cherry, JM ;

Davis, AP ;

Dolinski, K ;

Dwight, SS ;

Eppig, JT ;

Harris, MA ;

Hill, DP ;

Issel-Tarver, L ;

Kasarskis, A ;

Lewis, S ;

Matese, JC ;

Richardson, JE ;

Ringwald, M ;

Rubin, GM ;

Sherlock, G .

NATURE GENETICS, 2000, 25 (01) :25-29

[5] Finding undetected protein associations in cell signaling by belief propagation [J].

Bailly-Bechet, M. ;

Borgs, C. ;

Braunstein, A. ;

Chayes, J. ;

Dagkessamanskaia, A. ;

Francois, J. -M. ;

Zecchina, R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (02) :882-887

[6]

Baryshnikova A, 2010, NAT METHODS, V7, P1017, DOI [10.1038/nmeth.1534, 10.1038/NMETH.1534]

[7] Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease [J].

Beilina, Alexandria ;

Rudenko, Iakov N. ;

Kaganovich, Alice ;

Civiero, Laura ;

Chau, Hien ;

Kalia, Suneil K. ;

Kalia, Lorraine V. ;

Lobbestael, Evy ;

Chi, Ruth ;

Ndukwe, Kelechi ;

Ding, Jinhui ;

Nalls, Mike A. ;

Olszewski, Maciej ;

Hauser, David N. ;

Kumaran, Ravindran ;

Lozano, Andres M. ;

Baekelandt, Veerle ;

Greene, Lois E. ;

Taymans, Jean-Marc ;

Greggio, Elisa ;

Cookson, Mark R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (07) :2626-2631

[8] Computational solutions for omics data [J].

Berger, Bonnie ;

Peng, Jian ;

Singh, Mona .

NATURE REVIEWS GENETICS, 2013, 14 (05) :333-346

[9] SnapShot: Genetics of Parkinson's Disease [J].

Bras, Jose ;

Guerreiro, Rita ;

Hardy, John .

CELL, 2015, 160 (03) :570-U239

[10] Calcineurin determines toxic versus beneficial responses to α-synuclein [J].

Caraveo, Gabriela ;

Auluck, Pavan K. ;

Whitesell, Luke ;

Chung, Chee Yeun ;

Baru, Valeriya ;

Mosharov, Eugene V. ;

Yan, Xiaohui ;

Ben-Johny, Manu ;

Soste, Martin ;

Picotti, Paola ;

Kim, Hanna ;

Caldwell, Kim A. ;

Caldwell, Guy A. ;

Sulzer, David ;

Yue, David T. ;

Lindquist, Susan .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (34) :E3544-E3552

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