Homeostasis and Metabolism of Iron and Other Metal Ions in Neurodegenerative Diseases

Academic Background

Neurodegenerative diseases (such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease) are characterized by neuronal death and gradual loss of function, leading to the deterioration of cognitive, motor, and sensory functions. Metal ions (such as iron, manganese, copper, and zinc) play crucial roles in various physiological processes in the central nervous system, including energy metabolism, protein synthesis, DNA replication, membrane protein construction, myelin and neurotransmitter synthesis, etc. However, once the homeostasis of metal ions is disrupted, whether excessive or insufficient, it can be detrimental to neurons, leading to oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation, thereby promoting the development of neurodegenerative diseases.

Since the first observation of iron deposition in the brains of Parkinson’s disease (PD) patients in 1924, increasing research has shown that the abnormal accumulation or depletion of metal ions such as iron, manganese, copper, and zinc is closely related to the pathogenesis of these diseases. In particular, the recent discovery of novel forms of cell death such as ferroptosis and cuproptosis has provided new insights into the pathological mechanisms of neurodegenerative diseases.

Paper Source

This review was written by Leilei Chen, Qingqing Shen, Yingjuan Liu, Yunqi Zhang, Liping Sun, Xizhen Ma, Ning Song, and Junxia Xie from the Institute of Brain Science and Disease, Qingdao University, the Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, and the Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders. It was published in the journal Signal Transduction and Targeted Therapy in 2025. The paper aims to comprehensively review the research history, milestone events, upstream regulators, downstream effectors, and crosstalk of metal ions under both physiologic and pathologic conditions in neurodegenerative diseases.

Main Content of the Paper

Research History of Metal Ions in Neurodegenerative Diseases

The paper reviews the research history of metal ions, particularly iron, manganese, copper, and zinc, in neurodegenerative diseases since 1924. Early studies first observed iron deposition in PD patient brains using Perls’ and Turnbull staining techniques. Subsequent research confirmed the abnormal accumulation of iron, manganese, copper, and zinc in neurodegenerative diseases through methods like magnetic resonance imaging (MRI) and inductively coupled plasma mass spectrometry (ICP-MS). Notably, the discovery of ferroptosis and cuproptosis provides new perspectives on understanding the pathological mechanisms of neurodegenerative diseases.

Homeostasis and Metabolism of Metal Ions

The paper elaborates on the homeostatic regulation mechanisms of iron, manganese, copper, and zinc in the central nervous system. Iron, as an essential trace element, is involved in oxygen transport, DNA synthesis, mitochondrial respiration, and phospholipid synthesis. Iron homeostasis is regulated by multiple proteins and molecular mechanisms (such as transferrin receptor and divalent metal transporter 1), ensuring appropriate concentration and distribution across different brain regions, cells, and organelles. Similarly, the homeostasis of manganese, copper, and zinc is strictly controlled, with each metal ion having specific absorption, storage, and release mechanisms.

Therapeutic Effects of Metal Ion Chelators

The paper also discusses the potential therapeutic effects of various metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives, in treating neurodegenerative diseases. These chelators selectively capture metal ions and dissociate them from disease-related target sites, thereby minimizing side effects associated with broad-spectrum treatments. Although clinical trials have shown certain therapeutic effects of these chelators, their limitations cannot be ignored. For example, while the iron chelator Deferiprone exhibits neuroprotective effects in early-stage PD patients, its long-term efficacy and safety require further investigation.

Downstream Effectors and Roles of Metal Ions in Disease

Abnormal accumulation of metal ions can trigger multiple downstream effects, including oxidative stress, ferroptosis, cell senescence, and neuroinflammation. These effectors play critical roles in the pathogenesis of neurodegenerative diseases. For instance, iron and copper promote the generation of reactive oxygen species (ROS) via the Fenton reaction, leading to oxidative stress, which damages cell membranes, proteins, and nucleic acids. Additionally, novel forms of cell death such as ferroptosis and cuproptosis have been shown to be closely related to the occurrence and development of neurodegenerative diseases.

Significance and Value of the Study

This review not only provides a comprehensive understanding of the role of metal ions in the development of neurodegenerative diseases but also offers new perspectives for preventing and treating these diseases through modulation of metal ion homeostasis. By delving deeper into the regulatory mechanisms of metal ions under physiological and pathological conditions, future strategies may open new avenues for therapeutic intervention.

Highlights of the Study

1. Comprehensive Review: The paper systematically reviews the research history, milestone events, and mechanisms of metal ions in neurodegenerative diseases.
2. New Pathological Mechanisms: The discovery of ferroptosis and cuproptosis provides new insights into the pathogenesis of neurodegenerative diseases.
3. Therapeutic Potential: The paper discusses the potential of metal ion chelators in treating neurodegenerative diseases and points out their limitations in clinical trials.
4. Interdisciplinary Approach: The paper integrates multiple technical approaches, including molecular biology, imaging, and pathology, providing multi-level evidence for the role of metal ions in neurodegenerative diseases.

Conclusion

Through this review, we gain a deeper understanding of the critical role of metal ions in neurodegenerative diseases and new directions for future research. Further studies and modulation of metal ion homeostasis may bring new breakthroughs in the prevention and treatment of these diseases.