Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.
Copper Homeostasis and Cuproptosis in Neurodegenerative Diseases.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Weifang, CN · Author affiliation
School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, China.Location evidence
Boston, US · Author affiliation
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.Location evidence
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Original abstract
Copper is an essential trace element required for numerous enzymatic processes in the brain, including mitochondrial metabolism, antioxidant defense, and gene expression regulation. Recent studies have further implicated copper in a newly defined form of regulated cell death termed cuproptosis, providing a mechanistic framework for copper-dependent cytotoxicity. Increasing evidence indicates that copper dyshomeostasis is a common feature of major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), where it is associated with protein misfolding, redox imbalance, and neuronal vulnerability. Nevertheless, the mechanistic link between copper dysregulation and neuronal cell death remains incompletely defined. In this review, we systematically summarize the molecular mechanisms governing copper homeostasis and intracellular copper trafficking, while providing a timely, updated, and in-depth overview of the mechanistic basis and emerging biology of cuproptosis. We further comprehensively evaluate the current evidence linking copper dysregulation and cuproptosis-related pathways to neurodegenerative diseases, with particular emphasis on distinguishing mechanistic causation from pathological correlation. Importantly, we discuss current therapeutic strategies and emerging clinical efforts targeting copper metabolism, while highlighting the major challenges in defining the pathological significance and mechanistic contribution of cuproptosis in neurodegenerative diseases. Collectively, this review provides an updated framework for understanding the pathological significance and translational potential of cuproptosis in neurodegenerative diseases.