Heavy metal induced cellular proteostasis failure promotes neurodegeneration and therapeutic opportunities

Abstract

Exposure to heavy metals is a significant environmental risk factor for neurodegenerative diseases. Persistent exposure to heavy metals including lead, mercury, cadmium, manganese, copper, and arsenic are all examples of non-biodegradable, bioaccumulative toxicants that can cross the blood–brain barrier (BBB) and disrupt neuronal homeostasis. They trigger inflammatory reactions, calcium imbalance, excessive reactive oxygen species production, and mitochondrial dysfunction, all of which lead to neuronal damage. Mitochondrial injury is characterised by impaired membrane potential, reduced ATP production, and the release of pro-apoptotic factors, thereby worsening oxidative stress and jeopardising synaptic integrity. At the same time, heavy metals impair autophagic flux, block autophagosome–lysosome fusion and interfere with lysosomal acidification. Malfunction in key signalling pathways such as mTORC1, AMPK, and TFEB results in impaired proteostasis and the formation of harmful protein aggregates, including amyloid-β (Aβ), hyperphosphorylated tau, and α-synuclein—hallmarks of major neurodegenerative diseases. Furthermore, ongoing changes in gene expression linked to synaptic plasticity, inflammation, and neuronal survival driven by epigenetic modifications related to heavy metal exposure, include altered DNA methylation, histone modifications, and microRNA dysregulation. Age-related declines in mitochondrial turnover, antioxidant capacity, and lysosomal efficiency increase vulnerability to metal-induced toxicity, creating a synergistic environment that speeds up neurodegenerative processes. This review integrates current knowledge on the molecular mechanisms by which heavy metals compromise neuronal proteostasis, with particular emphasis on the the ubiquitin–proteasome system (UPS), ER proteostasis, unfolded protein response (UPR), molecular chaperones, selective autophagy, and lysosomal degradation, and explains how HMs co-ordinately disrupt these interconnected pathways to accelerate neurodegeneration. Clinical trial number Not applicable.