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Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington's disease
Open accessAbstract
Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine (polyQ) repeat in exon-1 in the Huntingtin gene (HTT). This results in misfolding and accumulation of the huntingtin (htt) protein, forming nuclear and cytoplasmic inclusions. HD is associated with dysregulation of gene expression as well as mitochondrial dysfunction. We hypothesized that by improving transcriptional regulation of genes necessary for energy metabolism, the HD motor phenotype would also improve. We therefore examined the protective effects of nicotinamide (NAM), a well-characterized water-soluble B vitamin that is an inhibitor of sirtuin1/class III NAD(+)-dependent histone deacetylase (HDAC). In this study, both mini-osmotic pumps and drinking water deliveries were tested at 250 mg NAM/kg/day, using the B6.HDR6/1 transgenic mouse model. Results were similar for both modes of delivery, and there was no evidence of toxicity. We found that NAM treatment increased mRNA levels of brain-derived neurotrophic factor (BDNF), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis. Protein levels of BDNF were also significantly increased. In addition, NAM treatment increased PGC-1α activation in HD mice, pointing to a possible mode of action as a therapeutic. Critically, NAM treatment was able to improve motor deficits associated with the HD phenotype, tested as time courses of open field, rotarod, and balance beam activities. These improvements were substantial, despite the fact that NAM did not appear to reduce htt aggregation, or to prevent late-stage weight loss. Our study therefore concludes that NAM or similar drugs may be beneficial in clinical treatment of the motor dysfunctions of HD, while additional therapeutic approaches must be added to combat the aggregation phenotype and overall physiological decline.
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“In different neurodegenerative mouse models including AD, HD, and the premature aging disease A-T, NAD+ augmentation increases the expression and activity of BDNF, leading to enhanced synaptic plasticity and function (Fang et al., 2016a; Hathorn et al., 2011; Liu et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Hathorn et al., 2011
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Metadata
- Authors
- Hathorn, T., Snyder-Keller, A., & Messer, A.
- Affiliations
- Albany Medical College (US)
- New York State Department of Health (US)
- Corresponding author
- Messer, Anne
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 41
- Issue
- 1
- Pages
- 43-50
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC2996046
- OpenAlex
- W2090796483
- Cited by
- 123
- References
- 53
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 8 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 12
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Neurological Disorders and Stroke (NS053912)
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, nicotinamide, PGC-1α, brain-derived neurotrophic factor, mitochondrial biogenesis, motor impairment, huntingtin aggregation, polyglutamine repeat, energy metabolism, neuroprotection
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Disease Models, Animal, Female, Humans, Huntington Disease, Male, Mice, Inbred C57BL, Mice, Transgenic, Niacinamide, Transcription Factors, Vitamin B Complex, Trans-Activators, Up-Regulation, Brain-Derived Neurotrophic Factor, Mitochondrial Diseases, Mice
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