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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Cholinergic neuronal defect without cell loss in Huntington's disease
Ruben Smith1, Hinfan Chung, Sara Rundquist
1Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden.
Human Molecular Genetics
|September 22, 2006
Summary
Huntington's disease (HD) affects cholinergic transmission, with reduced key proteins in mice and patients. This dysfunction, not cell death, impacts learning and memory, suggesting pro-cholinergic drugs may help treat HD.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansion in the huntingtin gene.
- While medium spiny neurons degenerate, large cholinergic neurons were thought to be spared.
- Neuronal dysfunction, not just cell death, is increasingly recognized in early-stage HD.
Purpose of the Study:
- To investigate the role of cholinergic transmission in Huntington's disease.
- To determine if cholinergic neurons are affected in HD models and patients.
- To explore potential therapeutic targets for HD.
Main Methods:
- Utilized a transgenic HD mouse model (R6/1) and post-mortem human brain tissues.
- Performed stereological analysis to assess neuronal loss.
- Quantified mRNA and protein levels of vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT).
- Measured acetylcholinesterase activity.
- Examined the expression of transcriptional regulator REST/NRSF.
- Assessed learning and memory deficits in R6/1 mice.
Main Results:
- No loss of cholinergic neurons was observed in the striatum or septum of R6/1 mice.
- Significant decreases in VAChT and ChAT mRNA and protein were found in the striatum and cortex of R6/1 mice.
- Reduced acetylcholinesterase activity was detected in the striatum of R6/1 mice.
- VAChT levels were also reduced in striatal tissue from HD patients, specifically in the striatum.
- REST/NRSF expression and localization remained unaltered in cholinergic neurons.
- R6/1 mice displayed severe learning and reference memory impairments.
Conclusions:
- Cholinergic transmission is demonstrably dysfunctional in both HD mouse models and human patients.
- This dysfunction, characterized by reduced VAChT and ChAT, occurs without cholinergic neuron loss.
- The findings support the rationale for investigating pro-cholinergic drugs as a therapeutic strategy for Huntington's disease.
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