Abstract: Neurodegenerative diseases, which mainly include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Wilson’s disease, and Huntington’s disease, are a group of disorders characterized by loss of neurons in the brain and spinal cord. However, the underlying pathogenetic mechanisms of these disorders remain unclear. The metal ion hypothesis is considered a possible cause of a variety of neurodegenerative diseases. This hypothesis posits that the homeostatic imbalance of metal ions leads to oxidative stress, neuroinflammation, excessive aggregation of pathological proteins, and other serious consequences in neurons. The powerful endogenous metal ion chelator metallothionein plays an important role in regulating metal ion homeostasis to alleviate neurodegenerative diseases. This article provides an overview of the pathogenesis of neurodegenerative diseases in relation to metal ions such as copper, iron, and zinc and the contribution of metallothionein to the regulation of metal ion homeostasis. The review focuses on the role of metal ions in the course of neurodegenerative diseases and the molecular mechanisms through which endogenous metallothionein ameliorates metal ion overload to alleviate neurodegenerative diseases. A thorough understanding of these molecular mechanisms can provide a theoretical foundation for the development of new therapeutic strategies, with the aim of more effectively treating these devastating diseases in the future.

Key words: Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, metal chelator, metal homeostasis, metal ion, metallothionein, neurodegenerative diseases, Parkinson’s disease, Wilson’s disease