Year: 2025
Type: dissertation
Abstract: Alzheimer’s disease, the most common form of dementia, represents a profound global health burden with urgent need for therapies. Metformin, the first-line drug to treat type II diabetes, is being explored as a potential therapy to treat Alzheimer’s disease following promising results from small-scale clinical trials in patients with mild cognitive impairment that suggest a beneficial role of metformin in ameliorating cognitive decline. However, in vitro experiments report metformin may potentially worsen the disease by increasing the generation of Amyloid-β (Aβ), a widely believed driving force of the pathogenesis of Alzheimer’s disease. To better understand metformin’s role in Alzheimer’s disease, a genetic screen was performed in an Aβproducing Drosophila model for metformin-regulated genes that modify Aβ-associated climbing defect. Multiple candidate suppressors and enhancers of Aβ toxicity were identified, and further validations suggested that the upregulation of rngo (rings lost), which encodes an extraproteasomal ubiquitin receptor, was the best suppressor of toxicity. Metformin could stabilise the rngo protein, possibly through a direct association. The human ortholog of rngo, DDI2 (DNA Damage Inducible 1 Homolog 2), plays a key role in maintaining protein homeostasis, which is in line with the results in flies that both metformin and rngo overexpression could enhance resistance against proteasomal stress. Metformin also suppressed the accumulation of poly-ubiquitinated proteins in human iPSC-derived neurons under proteasome inhibition. Collectively, this project identified a novel target and effector of metformin, rngo/DDI2, that may explain metformin’s benefits in ameliorating Aβ toxicity.
Author: Xu, Dongwei
Institution: University College London
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7112273720