Department of Neuroscience, Institute of Psychiatry, King's College London, CCBB, London SE5 9JU, UK.
Biochem Soc Trans. 2009 Dec;37(Pt 6):1270-5. doi: 10.1042/BST0371270.
HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.
亨廷顿病（HD）是一种迟发性遗传性神经退行性疾病，其特征是神经元功能障碍和死亡，尤其是在大脑皮层和纹状体的中型多棘神经元中。随后是进行性舞蹈病、痴呆和情绪功能障碍，最终导致死亡。HD 是由 HD 基因第一外显子中 CAG 重复扩增引起的，导致其蛋白产物 Htt（亨廷顿蛋白）中异常延长的多聚 Q（多谷氨酰胺）链。野生型 Htt 主要存在于细胞质中；然而，在 HD 中，Htt 的蛋白酶切 N 端片段在细胞质和核内形成不溶性沉积物，这引发了一个想法，即 mutHtt（突变 Htt）导致转录功能障碍。虽然已经提出了许多特定的转录因子和共因子作为 mutHtt 毒性的介质，但这些 Htt/转录因子相互作用与 HD 病理学之间的因果关系仍不清楚。以前的工作强调了 REST [RE1（抑制元件 1）-沉默转录因子]作为这样的转录因子之一。REST 是神经元基因的主要调节因子，抑制其表达。其许多直接靶基因已知或怀疑在 HD 发病机制中起作用，包括 BDNF（脑源性神经营养因子）。最近的证据还表明，REST 调节调节性 miRNA（microRNA）的转录，其中许多已知调节神经元基因表达，并且在 HD 中失调。因此，miRNA 的抑制构成了 REST 在 HD 中改变神经元转录组的第二个间接机制。我们将描述证据表明，由于 REST 与 mutHtt 之间相互作用的丧失导致 REST 调节子的破坏，可能是 HD 中广泛的基因表达失调的一个关键促成因素。
