Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA.
J Neuropathol Exp Neurol. 2010 Aug;69(8):817-27. doi: 10.1097/NEN.0b013e3181ea167f.
Huntington disease (HD) is a fatal neurodegenerative disease with no effective treatment. In the R6/1 mouse model of HD, environmental enrichment delays the neurologic phenotype onset and prevents cerebral volume loss by unknown molecular mechanisms. We examined the effects of environmental enrichment on well-characterized neuropathological parameters in a mouse model of HD. We found a trend toward preservation of downregulated neurotransmitter receptors in striatum of environmentally enriched mice and assessed possible enrichment-related modifications in gene expression using microarrays. We observed similar gene expression changes in R6/1 and R6/2 transgenic mice but found no specific changes in enrichment-related microarray expression profiles in either transgenic or wild-type mice. Furthermore, specific corrections in transprotein-induced transcriptional dysregulation in R6/1 mice were not detected by microarray profiling. However, gene-specific analyses suggested that long-term environmental enrichment may beneficially modulate gene expression dysregulation. Finally, environmental enrichment significantly decreased neuronal intranuclear inclusion load, despite unaffected transgene expression levels. Thus, the therapeutic effects of environmental enrichment likely contribute to decreasing aggregated polyglutamine protein levels without exerting strong effects on gene expression.
亨廷顿病（HD）是一种致命的神经退行性疾病，目前尚无有效治疗方法。在 HD 的 R6/1 小鼠模型中，环境富集通过未知的分子机制延迟神经表型发作并防止脑容量损失。我们研究了环境富集对 HD 小鼠模型中经过充分表征的神经病理学参数的影响。我们发现环境丰富的小鼠纹状体中下调的神经递质受体有保存的趋势，并使用微阵列评估了可能与富集相关的基因表达修饰。我们在 R6/1 和 R6/2 转基因小鼠中观察到类似的基因表达变化，但在任何转基因或野生型小鼠中都没有发现富集相关的微阵列表达谱的特定变化。此外，微阵列分析未检测到 R6/1 小鼠中转蛋白诱导的转录失调的特定校正。然而，基因特异性分析表明，长期环境富集可能有益地调节基因表达失调。最后，尽管转基因表达水平不受影响，环境富集仍显著降低了神经元核内包涵体负荷。因此，环境富集的治疗效果可能有助于降低聚集的多聚谷氨酰胺蛋白水平，而对基因表达没有强烈影响。
