한빛사논문
- 조회290
Adam D. Hudgins,1,8 Shiyi Zhou,2,8 Rachel N. Arey,2,7 Michael G. Rosenfeld,3,4 Coleen T. Murphy,2,5,* and Yousin Suh 1,6,9,*
1Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA
2Department of Molecular Biology, Princeton University, Princeton, NJ, USA
3Department of Medicine, School of Medicine, University of California, La Jolla, CA, USA
4Howard Hughes Medical Institute, University of California, La Jolla, CA, USA
5LSI Genomics, Princeton University, Princeton, NJ, USA
6Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
7Present address: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
8These authors contributed equally
9Lead contact
*Corresponding authors: correspondence to Coleen T. Murphy or Yousin Suh
Abstract
Genome-wide association studies (GWASs) have uncovered over 75 genomic loci associated with risk for late-onset Alzheimer’s disease (LOAD), but identification of the underlying causal genes remains challenging. Studies of induced pluripotent stem cell (iPSC)-derived neurons from LOAD patients have demonstrated the existence of neuronal cell-intrinsic functional defects. Here, we searched for genetic contributions to neuronal dysfunction in LOAD using an integrative systems approach that incorporated multi-evidence-based gene mapping and network-analysis-based prioritization. A systematic perturbation screening of candidate risk genes in Caenorhabditis elegans (C. elegans) revealed that neuronal knockdown of the LOAD risk gene orthologs vha-10 (ATP6V1G2), cmd-1 (CALM3), amph-1 (BIN1), ephx-1 (NGEF), and pho-5 (ACP2) alters short-/intermediate-term memory function, the cognitive domain affected earliest during LOAD progression. These results highlight the impact of LOAD risk genes on evolutionarily conserved memory function, as mediated through neuronal endosomal dysfunction, and identify new targets for further mechanistic interrogation.
논문정보
- Research article
- 2024년 04월 (BRIC 등록일 2024-05-16)
- 국외 연구진
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