Recently, the research group of Prof. Junxia Xie, Prof. Ning Song Ning and Associate Prof. Leilei Chen from the Institute of Brain Science and Disease has published a review article titled "Homeostasis and metabolism of iron and other metal ions in the neurodegenerative diseases" in the Nature sub-journal “Signal Transduction and Targeted Therapy” (STTT, with an impact factor 40.8), which has been reported by brainnews in the section of Frontier Progress in Brain Science on February 8, 2025. The first author of this review is Leilei Chen, who is a specially-appointed professor of Institute of Brain Science and Disease, and a recipient of Natural Science Foundation of Shandong Province-Outstanding Youth Foundation. Professor Song Ning, the leader of the young innovation team of higher education institutions in Shandong province, is listed as a co-author. The corresponding author of this review is Prof. Junxia Xie, who is the dean of the Institute of Brain Science and Disease, expert receiving special government allowance from the state council, national outstanding science and technology worker, vice-supervisor of the Chinese Neuroscience Society, and Taishan scholar of Shandong province. The Institute of Brain Science and Disease is listed as both the primary and corresponding affiliation. This work was supported by grants from National Natural Science Foundation of China, Natural Science Foundation of Shandong Province-Outstanding Youth Foundation, and Qingdao Natural Science Foundation.

Metal ions, such as iron, manganese, copper, zinc, etc.,play crucial rolesin various physiological processes in the central nervous system, including energy metabolism, protein synthesis, DNA replication, membrane protein construction, myelin and neurotransmittersynthesis, and so on.The homeostasis of metal ions in the brain is regulated by multiple proteins and molecular mechanisms, which work together to control the processed of absorption, storage and release, thereby maintaining the appropriate concentration and distribution among different brain regions, cells and organelles.However, once the homeostasis of these metal ions is disrupted,eitherdepletionor accumulation,they can affect the activity of enzymes involved in neurodegenerative diseases since they serve as important co-factors for enzymes.Since iron deposits in the brains of patients with Parkinson’s disease (PD) was first observed in 1924, the relationship between ion dyshomeostasis and neurodegenerative diseases has attracted more and more attentions. This reviewintroducedthe research history and milestone events of study on mental ions (iron, manganese, copper, and zinc) in neurodegenerative diseases, including PD, Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). And then, itdiscussed upstream regulators, downstream effector,andcrosstalk of mental ions homeostasisfrombrain regions, cells to organelles in physiology and neurodegenerative diseases. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed.This review not only provides a comprehensive understanding of the role of metal ions in disease development but also offers perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.

Crosstalk between dysregulation of metal ions and pathological proteins in neurodegenerative diseases