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Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitropropionic acid
Abstract
The mechanisms of delayed onset and cell death in Huntington's disease (HD) are unknown. One possibility is that a genetic defect in energy metabolism may result in slow excitotoxic neuronal death. Therefore, we examined the effects of age on striatal lesions produced by local administration of the mitochondrial toxin 3-nitropropionic acid in rats. In vivo chemical shift magnetic resonance imaging showed marked increases in striatal lactate concentrations that significantly correlated with increasing age. Histologic and neurochemical studies showed a striking age dependence of the lesions, with 4- and 12-month-old animals being much more susceptible than 1-month-old animals. Continuous systemic administration of low doses of 3-nitropropionic acid for 1 month resulted in striatal lesions showing growth-related changes in dendrites of striatal spiny neurons using the Golgi technique. These results show that a known mitochondrial toxin can produce selective axon-sparing striatal lesions showing both the age dependence and striatal spiny neuron dendritic changes that characterize HD.
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“This specific down-regulation of mitochondrial processes in aged striatum could help to explain previous observations demonstrating selective vulnerability to mitochondrial toxins and stresses in the striatum of old animals (Brouillet et al., 1993; Patki et al., 2009).”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Brouillet et al., 1993
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Metadata
- Authors
- Brouillet, E., Jenkins, B. G., Hyman, B. T., Ferrante, R. J., Kowall, N. W., Srivastava, R., Roy, D. S., Rosen, B. R., & Beal, M. F.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- Corresponding author
- Beal, M. Flint
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1993-01
- Volume
- 60
- Issue
- 1
- Pages
- 356-359
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1983729920
- Cited by
- 367
- References
- 16
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 11 · 2015: 3 · 2014: 11 · 2013: 6 · 2012: 10
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (16367)
- National Institute of Neurological Disorders and Stroke (NS10828)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Huntington's disease, 3-nitropropionic acid, striatum, age-related susceptibility, mitochondrial toxins, dendritic changes, lactate, energy metabolism, excitotoxicity, neurodegeneration
- MeSH terms
- Adenosine Triphosphate, Aging, Corpus Striatum, Lactates, Mitochondria, Neurotoxins, Nitro Compounds, Propionates, Lactic Acid, In Vitro Techniques
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