A systems biology-based identification and in vivo functional screening of Alzheimer's disease risk genes reveal modulators of memory function

Adam D Hudgins; Shiyi Zhou; Rachel N Arey; Michael G Rosenfeld; Coleen T Murphy; Yousin Suh

doi:10.1016/j.neuron.2024.04.009

A systems biology-based identification and in vivo functional screening of Alzheimer's disease risk genes reveal modulators of memory function

Neuron. 2024 Apr 25:S0896-6273(24)00247-2. doi: 10.1016/j.neuron.2024.04.009. Online ahead of print.

Authors

Adam D Hudgins¹, Shiyi Zhou², Rachel N Arey², Michael G Rosenfeld³, Coleen T Murphy⁴, Yousin Suh⁵

Affiliations

¹ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA.
² Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
³ Department of Medicine, School of Medicine, University of California, La Jolla, CA, USA; Howard Hughes Medical Institute, University of California, La Jolla, CA, USA.
⁴ Department of Molecular Biology, Princeton University, Princeton, NJ, USA; LSI Genomics, Princeton University, Princeton, NJ, USA. Electronic address: ctmurphy@princeton.edu.
⁵ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: ys3214@cumc.columbia.edu.

PMID: 38692279
DOI: 10.1016/j.neuron.2024.04.009

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.

Keywords: Alzheimer’s disease; C. elegans; genetics; post-GWAS; systems biology.