Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C
Open accessAbstract
Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not significantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progressively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt-mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.
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The normal huntingtin protein is multifunctional, with roles in transcriptional regulation, vesicular transport, and synaptic transmission.
“The normal huntingtin protein is multifunctional, with roles in transcriptional regulation, vesicular transport, and synaptic transmission [164,165,166].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [165]
The Discussion (page not available in our copy) describes Htt interacting with transcription factors and sequestering the transcriptional repressor REST, supporting a role in transcriptional regulation. The Introduction links mutant Htt to synaptic-transmission dysfunction, but the paper does not establish vesicular transport or synaptic transmission as roles of normal Htt. (LLM, conf=0.84)
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- Authors
- Peng, C., Zhu, G., Liu, X., & Li, H.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Corresponding author
- Liu, Xiangqian
- Li, He
- ORCID
- Liu, Xiangqian
- Venue
- Neuroscience Bulletin
- Published
- 2018-04-30
- Volume
- 34
- Issue
- 5
- Pages
- 747-758
- ISSN
- 1995-8218 (ISSN-L)
- 1673-7067
- PMC
- PMC6129247
- OpenAlex
- W2800614809
- Cited by
- 16
- References
- 113
- Citations by year
- 2025: 2 · 2024: 4 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 2
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuroscience Bulletin (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81371417)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Huntington's disease, mutant huntingtin, SV2C, SV2A, SV2B, polyglutamine expansion, synaptic dysfunction, transcriptional repression, basal ganglia, hippocampus, transgenic mouse model, N2a cells
- MeSH terms
- Huntingtin Protein, Aging, Animals, Brain, Membrane Glycoproteins, Mice, Transgenic, Mutation, Nerve Tissue Proteins, RNA, Messenger, Transcription, Genetic, Gene Expression, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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