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Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease
Open accessAbstract
There are several interrelated mechanisms involving iron, dopamine, and neuromelanin in neurons. Neuromelanin accumulates during aging and is the catecholamine-derived pigment of the dopamine neurons of the substantia nigra and norepinephrine neurons of the locus coeruleus, the two neuronal populations most targeted in Parkinson's disease. Many cellular redox reactions rely on iron, however an altered distribution of reactive iron is cytotoxic. In fact, increased levels of iron in the brain of Parkinson's disease patients are present. Dopamine accumulation can induce neuronal death; however, excess dopamine can be removed by converting it into a stable compound like neuromelanin, and this process rescues the cell. Interestingly, the main iron compound in dopamine and norepinephrine neurons is the neuromelanin-iron complex, since neuromelanin is an effective metal chelator. Neuromelanin serves to trap iron and provide neuronal protection from oxidative stress. This equilibrium between iron, dopamine, and neuromelanin is crucial for cell homeostasis and in some cellular circumstances can be disrupted. Indeed, when neuromelanin-containing organelles accumulate high load of toxins and iron during aging a neurodegenerative process can be triggered. In addition, neuromelanin released by degenerating neurons activates microglia and the latter cause neurons death with further release of neuromelanin, then starting a self-propelling mechanism of neuroinflammation and neurodegeneration. Considering the above issues, age-related accumulation of neuromelanin in dopamine neurons shows an interesting link between aging and neurodegeneration.
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“Indeed, elevated iron in the CNS is associated with ND (reviewed in [133] and [134]), possibly at levels higher than with normal aging [133].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [134]
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Metadata
- Authors
- Zucca, F. A., Segura-Aguilar, J., Ferrari, E., Muñoz, P., Paris, I., Sulzer, D., Sarna, T., Casella, L., & Zecca, L.
- Affiliations
- Institute of Biomedical Technologies (IT)
- University of Chile (CL)
- Universidad Santo Tomás (CL)
- Columbia University Irving Medical Center (US)
- Jagiellonian University (PL)
- University of Pavia (IT)
- Corresponding author
- Zecca, Luigi
- ORCID
- Venue
- Progress in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 155
- Pages
- 96-119
- ISSN
- 0301-0082 (ISSN-L)
- PMC
- PMC4826627
- OpenAlex
- W1913653254
- Cited by
- 659
- References
- 350
- Citations by year
- 2026: 43 · 2025: 59 · 2024: 58 · 2023: 73 · 2022: 74 · 2021: 72 · 2020: 70 · 2019: 77 · 2018: 53 · 2017: 46
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Progress in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Drug Abuse (P01DA010154, R01DA007418)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- neuromelanin, iron, dopamine, brain aging, Parkinson's disease, substantia nigra, locus coeruleus, noradrenergic neurons, oxidative stress, metal chelation, neuroinflammation, microglial activation, neurodegeneration, redox homeostasis
- MeSH terms
- Aging, Animals, Dopamine, Humans, Iron, Melanins, Parkinson Disease
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