β-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis.
β-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis.
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DOI：
10.1523/jneurosci.3332-11.2011
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发表时间：
2011-11-16
期刊：
影响因子：
--
通讯作者：
Rothstein JD
中科院分区：
文献类型：
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作者：
Gao Y;Perkins EM;Clarkson YL;Tobia S;Lyndon AR;Jackson M;Rothstein JD
编码β-III血影蛋白的基因突变引起脊髓小脑共济失调5型（SCA 5），这是一种神经退行性疾病，其特征为分子层进行性变薄、浦肯野细胞丢失和运动缺陷增加。缺乏全长β-III血影蛋白（β-III−/−）的小鼠表现出类似的表型。缺乏β-III血影蛋白的浦肯野细胞的体外和体内分析揭示了β-III血影蛋白在浦肯野细胞形态发育中的关键作用。β-III−/−小鼠的浦肯野细胞中正常有序的树突分支被破坏，特别是表现出单平面组织的丧失，平均树突直径较小，浦肯野细胞棘和突触密度降低。早期形态缺陷似乎影响树突状，但不是轴突，蛋白质的分布。这项研究证实，与疾病发病机制相关的分子层变薄是浦肯野细胞树突状变性的结果，因为与5-6周龄的β-III −/−小鼠相比，8个月大的β-III −/−小鼠的浦肯野细胞的树突体积、表面积和总树突长度急剧减少。这些发现强调了β-III血影蛋白在树突生物学中的关键作用，并与β-III−/−小鼠的早期发育缺陷一致，异常的浦肯野细胞树突形态可能是疾病发病机制的基础。
Mutations in the gene encoding β-III spectrin give rise to spinocerebellar ataxia type 5 (SCA5), a neurodegenerative disease characterized by progressive thinning of the molecular layer, loss of Purkinje cells and increasing motor deficits. A mouse lacking full-length β-III spectrin (β-III−/−) displays a similar phenotype. In vitro and in vivo analyses of Purkinje cells lacking β-III spectrin, reveal a critical role for β-III spectrin in Purkinje cell morphological development. Disruption of the normally well-ordered dendritic arborization occurs in Purkinje cells from β-III−/− mice, specifically showing a loss of monoplanar organization, smaller average dendritic diameter and reduced densities of Purkinje cell spines and synapses. Early morphological defects appear to affect distribution of dendritic, but not axonal, proteins. This study confirms that thinning of the molecular layer associated with disease pathogenesis is a consequence of Purkinje cell dendritic degeneration, as Purkinje cells from 8-month old β-III−/− mice have drastically reduced dendritic volumes, surface areas and total dendritic lengths compared to 5–6 week old β-III−/− mice. These findings highlight a critical role of β-III spectrin in dendritic biology and are consistent with an early developmental defect in β-III−/− mice, with abnormal Purkinje cell dendritic morphology potentially underlying disease pathogenesis.