期刊
ISCIENCE
卷 20, 期 -, 页码 248-+出版社
CELL PRESS
DOI: 10.1016/j.isci.2019.09.026
关键词
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资金
- U.S. Dept. of Veteran Affairs [2 I01 BX001655]
- Inglewood Scholars Program
- National Institute on Aging (NIA/NIH) [2P01AG012411-17A1]
- Windgate Foundation
- Philip R. Jonsson Foundation
Diagnosis of neurodegenerative diseases hinges on seed'' proteins detected in disease-specific aggregates. These inclusions contain diverse constituents, adhering through aberrant interactions that our prior data indicate are nonrandom. To define preferential protein-protein contacts mediating aggregate coalescence, we created click-chemistry reagents that cross-link neighboring proteins within human, APPSw-driven, neuroblastoma-cell aggregates. These reagents incorporate a biotinyl group to efficiently recover linked tryptic-peptide pairs. Mass-spectroscopy outputs were screened for all possible peptide pairs in the aggregate proteome. These empirical linkages, ranked by abundance, implicate a protein- adherence network termed the ``aggregate contactome.'' Critical hubs and hub-hub interactions were assessed by RNAi-mediated rescue of chemotaxis in aging nematodes, and aggregation-driving properties were inferred by multivariate regression and neural-network approaches. Aspirin, while disrupting aggregation, greatly simplified the aggregate contactome. This approach, and the dynamic model of aggregate accrual it implies, reveals the architecture of insoluble-aggregate networks and may reveal targets susceptible to interventions to ameliorate protein-aggregation diseases.
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