Cellular and circuit mechanisms underlying spinocerebellar ataxias
Cellular and circuit mechanisms underlying spinocerebellar ataxias
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DOI：
10.1113/jp271897
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发表时间：
2016-08-15
影响因子：
5.5
通讯作者：
Otis, Thomas S.
中科院分区：
文献类型：
--
作者：
Meera, Pratap;Pulst, Stefan M.;Otis, Thomas S.
退行性共济失调是一种常见的神经退行性疾病，每10万人中约有20人受到影响。常染色体显性遗传性脊髓小脑共济失调（SCA）是由单个基因的多种蛋白质编码突变（单核苷酸改变、缺失和扩增）引起的。受影响的基因编码质膜和细胞内离子通道、膜受体、蛋白激酶、蛋白磷酸酶和功能未知的蛋白质。虽然SCA连锁基因是相当多样化的，但它们有两个关键特征：第一，它们在小脑浦肯野神经元（PN）中高度表达，但不完全表达;第二，当突变时，它们最终导致PN的变性。在这篇综述中，我们总结了共济失调相关的PN神经生理学的变化，已观察到在各种小鼠基因敲除线和人类SCA的转基因模型。我们还强调了新出现的证据表明，改变代谢型谷氨酸受体信号转导和破坏钙稳态PN形成一个共同的，早期的病理生理机制在SCA。总之，这些发现表明，异常钙信号传导和PN神经生理学的深刻变化先于PN细胞丢失，并可能导致小脑回路功能障碍，解释了该疾病的共济失调特征的行为体征。
Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs. In this review we summarize ataxia-related changes in PN neurophysiology that have been observed in various mouse knockout lines and in transgenic models of human SCA. We also highlight emerging evidence that altered metabotropic glutamate receptor signalling and disrupted calcium homeostasis in PNs form a common, early pathophysiological mechanism in SCAs. Together these findings indicate that aberrant calcium signalling and profound changes in PN neurophysiology precede PN cell loss and are likely to lead to cerebellar circuit dysfunction that explains behavioural signs of ataxia characteristic of the disease.