Klockgether T, Evert B
Dept of Neurology, University of Bonn, Germany.
Trends Neurosci. 1998 Sep;21(9):413-8. doi: 10.1016/s0166-2236(98)01315-0.
The hereditary ataxias are a group of inherited neurodegenerative disorders characterized by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. Recent molecular research has led not only to the discovery of a number of causative mutations, but also shed light on the likely mechanisms by which these mutations cause the respective phenotypes. In Friedreich's ataxia (FRDA), the most common type of autosomal recessive ataxia, the loss of a mitochondrial protein, frataxin, results in overload of mitochondrial iron and oxidative stress. The autosomal dominant ataxias, spinocerebellar ataxia type I (SCAI), SCA2, SCA3 and SCA7, are caused by inheritance of an unstable, expanded CAG trinucleotide repeat. These disorders are assumed to be due to a novel deleterious function of the extended polyglutamine sequences within the proteins encoded by the respective genes. Recent observations in transgenic mice and in human post-mortem tissue suggest that the extended proteins are transported into the nucleus of neurons where they form intranuclear inclusions that disrupt normal nuclear function. In another group of dominant disorders, episodic ataxia type I and type 2 (EA-I, EA-2) and SCA6, the mutations affect genes that code for ion channels.
遗传性共济失调是一组遗传性神经退行性疾病，其特征为进行性共济失调，由小脑及其传入和传出连接的退化所致。最近的分子研究不仅发现了许多致病突变，还揭示了这些突变导致各自表型的可能机制。在常染色体隐性共济失调最常见的类型——弗里德赖希共济失调（FRDA）中，线粒体蛋白frataxin的缺失导致线粒体铁过载和氧化应激。常染色体显性共济失调，如脊髓小脑共济失调1型（SCAI）、SCA2、SCA3和SCA7，是由不稳定的、扩展的CAG三核苷酸重复序列遗传所致。这些疾病被认为是由于各自基因编码的蛋白质中延伸的多聚谷氨酰胺序列具有新的有害功能。最近在转基因小鼠和人类尸检组织中的观察表明，延伸的蛋白质被转运到神经元细胞核中，在那里形成核内包涵体，破坏正常的核功能。在另一组显性疾病中，发作性共济失调1型和2型（EA-I、EA-2）以及SCA6，突变影响编码离子通道的基因。
