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Record W2128471322 · doi:10.1073/pnas.1318306111

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

2014· article· en· W2128471322 on OpenAlexaff
Alexandria Beilina, Iakov N. Rudenko, Alice Kaganovich, Laura Civiero, Hien Chau, Suneil K. Kalia, Lorraine V. Kalia, Evy Lobbestael, Ruth Chia, Kelechi Ndukwe, Mike A. Nalls, Maciej B. Olszewski, David N. Hauser, Ravindran Kumaran, Andrés M. Lozano, Veerle Baekelandt, Lois E. Greene, Jean‐Marc Taymans, Elisa Greggio, Mark Cookson, Vincent Plagnol, María Martínez, Dena G. Hernandez, Manu Sharma, Una‐Marie Sheerin, Mohamad Saad, Javier Simón‐Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Roger A. Barker, Yoav Ben‐Shlomo, Henk W. Berendse, Daniela Berg, Kailash P. Bhatia, Rob M.A. de Bie, Alessandro Biffi, Zoltán Bochdanovits, Michael von Bonin, José Brás, Kathrin Brockmann, Janet Brooks, David J. Burn, Gavin Charlesworth, Honglei Chen, Sean Chong, Carl E Clarke, Jonathan M. Cooper, Jean‐Christophe Corvol, Carl Counsell, Philippe Damier, Jean‐François Dartigues, Panos Deloukas, Günther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, F. Durif, Alexandra Dürr, Sarah Edkins, Jonathan Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, J. Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Ómar Gústafsson, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert R. Hollenbeck, Janice L. Holton, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah Hunt, Johanna Huttenlocher, Thomas Illig, Helmholtz Zentrum München, Pálmi V. Jónsson, Jean‐Charles Lambert, Cordelia Langford, Andrew J. Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Alisdair McNeill, Catriona Moorby, M. Elyse Moore, Huw R. Morris, Karen Morrison, Ese Mudanohwo, Sean S. O’Sullivan, Justin Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamás Révész, Olaf Rieß, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony H.V. Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Colin Smith, Chris C. A. Spencer, Hreinn Stefánsson, Stacy Steinberg, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, François Tison, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Daan C. Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams‐Gray, Sophie Winder‐Rhodes, Kāri Stefánsson, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew Singleton, Nicholas Wood, Patrick F. Chinnery, Luigi Ferrucci, Robert Johnson, Dan L. Longo, Elisa Majounie, Michael A. Nalls, Richard F. OʼBrien, Juan C. Troncoso, Marcel van der Brug, H. Ronald Zielke, Alan B. Zonderman

Bibliographic record

VenueProceedings of the National Academy of Sciences · 2014
Typearticle
Languageen
FieldMedicine
TopicParkinson's Disease Mechanisms and Treatments
Canadian institutionsUniversity of TorontoUniversity Health Network
FundersNational Institute of Neurological Disorders and StrokeNational Institutes of HealthMedical Research CouncilParkinson's UKWellcome Trust
KeywordsGenome-wide association studyComputational biologyGeneticsGenetic associationDiseaseParkinson's diseaseIdentification (biology)BiologyLRRK2Single-nucleotide polymorphismMedicineGeneGenotypeInternal medicine

Abstract

fetched live from OpenAlex

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein-protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G-associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame machine prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.

metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.001
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: Bench or experimental
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.001
Threshold uncertainty score0.005

Distilled classifier scores by category (both heads)

CategoryCodexGemma
Metaresearch0.0000.001
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0010.000
Science and technology studies0.0010.000
Scholarly communication0.0000.000
Open science0.0000.001
Research integrity0.0000.000
Insufficient payload (model declined to judge)0.0010.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.036
GPT teacher head0.309
Teacher spread0.273 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations367
Published2014
Admission routes1
Has abstractyes

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Same venueProceedings of the National Academy of SciencesSame topicParkinson's Disease Mechanisms and TreatmentsFrench-language works237,207