Cited by 659Parkinson's Disease Mechanisms and TreatmentsNeurological diseases and metabolismIron Metabolism and Disorders

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

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Zucca, Fabio A., Segura-Aguilar, Juan, Ferrari, Emanuele, Muñoz, Patricia, Paris, Irmgard, Sulzer, David, Sarna, Tadeusz, Casella, Luigi +1 more·2017·Progress in Neurobiology

Abstract

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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Research works printed but not linked: 4

  1. Brilliant MH Nordlund JJ Boissy RE Hearing VJ King RA Oetting WS Ortonne J-P Molecular Regulation of Melanin Formation: Melanosome Transport Proteins The Pigmentary System: Physiology and Pathophysiology 2006 Second edition Malden, MA, USA Blackwell Publishing 230 241
  2. Jimbow K Quevedo WC Fitzpatrick TB Szabo G Freeberg IA Eisen AZ Wolf K Austen KF Goldsimth LA Katz SI Fitzpatrick TB Biology of Melanocytes Fiotzpatrick’s Dermatology in General Medicine 1999 5th edition New York McGraw Hill 192 220
  3. Tiekink ERT Zukerman-Schpector J The Importance of Pi-Interactions in Crystal Engineering: Frontiers in Crystal Engineering 2012 John Wiley & Sons
  4. Zucca FA Cupaioli FA Zecca L Milardi D Rizzarelli E The role of iron in neurodegeneration Neurodegeneration: metallostasis and proteostasis 2011 Cambridge RSC Publishing 174 211

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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
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
2017-08
Volume
155
Pages
96-119
ISSN
0301-0082 (ISSN-L)
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 · 2016: 30 · 2015: 2 · 2012: 1
FWCI
5.75
Type
journal article
Language
en
Open access
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 › 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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