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An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration
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Journal Article
An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration
2025
Overview
Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer’s disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in
Drosophila
. We also measured proteomics, phosphoproteomics, and metabolomics in
Drosophila
models of Alzheimer’s disease and identified Alzheimer’s genetic variants that modify gene expression in disease-vulnerable neurons in humans. We then used a network model to integrate these data with previously published Alzheimer’s disease proteomics, lipidomics and genomics. Here, we computationally predict and experimentally confirm how
HNRNPA2B1
and
MEPCE
enhance toxicity of the tau protein, a pathological feature of Alzheimer’s disease. Furthermore, we demonstrated that the screen hits
CSNK2A1
and
NOTCH1
regulate DNA damage in
Drosophila
and human stem cell-derived neural progenitor cells. Our study identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer’s disease.
In this study, Leventhal et al. integrate multi-omic data from human and Drosophila models of Alzheimer’s disease to define regulators of age-associated neurodegeneration in Alzheimer’s disease and the pathways through which they act.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/89
/ 45/100
/ 45/43
/ 45/47
/ 45/91
/ 82/80
/ Alzheimer Disease - genetics
/ Alzheimer Disease - metabolism
/ Alzheimer Disease - pathology
/ Animals
/ Drosophila melanogaster - genetics
/ Drosophila Proteins - genetics
/ Drosophila Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Insects
/ Nerve Degeneration - genetics
/ Receptor, Notch1 - metabolism
/ Science
/ Toxicity
