Soong Bing-wen, Paulson Henry L
Department of Neurology, National Yang-Ming University School of Medicine, The Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Curr Opin Neurol. 2007 Aug;20(4):438-46. doi: 10.1097/WCO.0b013e3281fbd3dd.
Here we discuss recent advances regarding the molecular genetic basis of dominantly inherited ataxias.
Important recent observations include insights into the mechanisms by which expanded polyglutamine causes cerebellar degeneration; new findings regarding how noncoding expansions may cause disease; the discovery that conventional (i.e. nonrepeat) mutations underlie recently identified ataxias; and growing recognition that multiple biological pathways, when perturbed, can cause cerebellar degeneration.
The dominant ataxias, also known as spinocerebellar ataxias, continue to grow in number. Here we review the major categories of spinocerebellar ataxias: expanded polyglutamine ataxias; noncoding repeat ataxias; and ataxias caused by conventional mutations. After discussing features shared by these disorders, we present recent evidence supporting a toxic protein mechanism for the polyglutamine spinocerebellar ataxias and the recognition that both protein misfolding and perturbations in nuclear events represent key events in pathogenesis. Less is known about pathogenic mechanisms in spinocerebellar ataxias due to noncoding repeats, though a toxic RNA effect remains possible. Newly discovered, conventional mutations in spinocerebellar ataxias suggest a wide range of biological pathways can be disrupted to cause progressive ataxia. Finally, we discuss how new mechanistic insights can drive the push toward preventive treatment.
本文讨论了显性遗传性共济失调分子遗传基础的最新进展。
近期重要的观察结果包括对多聚谷氨酰胺扩增导致小脑变性机制的深入了解；关于非编码重复序列如何导致疾病的新发现；发现传统（即非重复）突变是最近鉴定出的共济失调的基础；以及越来越多的认识是，多种生物学途径受到干扰时可导致小脑变性。
显性共济失调，也称为脊髓小脑共济失调，其数量持续增加。本文综述了脊髓小脑共济失调的主要类别：多聚谷氨酰胺扩增型共济失调；非编码重复型共济失调；以及由传统突变引起的共济失调。在讨论了这些疾病的共同特征后，我们展示了支持多聚谷氨酰胺脊髓小脑共济失调毒性蛋白机制的最新证据，以及对蛋白质错误折叠和核事件紊乱是发病机制关键事件的认识。对于非编码重复序列导致的脊髓小脑共济失调的致病机制了解较少，尽管毒性RNA效应仍有可能。脊髓小脑共济失调中新发现的传统突变表明，多种生物学途径可能被破坏，从而导致进行性共济失调。最后，我们讨论了新的机制见解如何推动预防治疗的发展。
