Metformin promotes broad neuroprotection and proteostatic resilience via rngo/DDI2 stabilisation

Abstract

Alzheimers disease (AD) is one of the most common age-related causes of death, with limited effective disease-modifying treatments. Although metformin shows promise as a disease-modifying agent for AD, its molecular mechanism--specifically how it confers neuroprotection despite potentially increasing amyloid-beta (A{beta}) load--remains obscure. Here, we demonstrate that metformin functions as a pharmacological activator of the ubiquitin-binding protease rngo/DDI2. Through a genetic screen in Drosophila, we identified rngo/DDI2 as a potent suppressor of A{beta} toxicity. We provide in silico and genetic evidence that metformin interacts with the conserved D257 residue of the rngo/DDI2 RVP domain, inducing homodimerisation and subsequent protein stabilisation. This activation boosts proteasome activity in the presence of A{beta} preferentially clearing highly abundant proteins to preserve proteostasis. Crucially, this intervention is broadly effective; rngo/DDI2 upregulation robustly suppresses toxicity in models of TDP-43 and C9orf72-repeat expansion pathology, indicating a generalised mechanism of neuroprotection. Supported by human iPSC data and evidence of DDI2 depletion in AD patient brains, our results identify rngo/DDI2 as a conserved regulator of neuronal resilience. We propose that directly targeting DDI2 stabilisation represents a novel, broadly applicable therapeutic strategy to counteract proteotoxic stress across a broad spectrum of neurodegenerative diseases.