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Cited by 48Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingMitochondrial Function and Pathology

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

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Watanabe, Hirohisa, Dijkstra, Johannes M., Nagatsu, Toshiharu·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms25042009PMC PMC10888576
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Abstract

The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

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  • SNc DA neuron dysfunction is a known predisposing factor for neurodegeneration in PD.

    “Since SNc DA neuron dysfunction is a known predisposing factor for neurodegeneration in PD (Watanabe et al. 2024)”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Watanabe et al. 2024

    Section 2.8 (page unavailable) says SNc dopamine neurons are especially vulnerable to degeneration in PD, supporting the claim’s link between these neurons and neurodegeneration. It does not establish that their dysfunction is a known predisposing factor; it says PD usually does not start in these neurons and that other factors act on their vulnerability. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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200 of 201 shown

Cited by

Sorted by citations

Authors
Watanabe, H., Dijkstra, J. M., & Nagatsu, T.
Affiliations
Fujita Health University (JP)
Corresponding author
Watanabe, Hirohisa
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-02-07
Volume
25
Issue
4
Pages
2009
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms25042009
PMC
PMC10888576
OpenAlex
W4391612323
Cited by
48
References
11
Citations by year
2026: 22 · 2025: 16 · 2024: 10
FWCI
3.08
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Preprints.org (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Japan Society for the Promotion of Science (JP22K07508)
  • Research Committee of Ataxia, Health Labor Sciences Research Grant, Ministry of Health, Labor and Welfare, Japan (JPMH20FC1041)
  • Japan Agency for Medical Research and Development (22dk0207055h0002, JP21wm0425016)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Parkinson's disease, substantia nigra pars compacta, dopaminergic neurons, oxidative stress, dopamine metabolism, cytosolic calcium oscillations, calbindin, neuromelanin, mitochondrial calcium, mitochondrial damage, bioenergetics, aging, neurodegeneration, neuroprotection
MeSH terms
Dopamine, Energy Metabolism, Humans, Parkinson Disease, Substantia Nigra, Oxidative Stress, Dopaminergic Neurons

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