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首页> 外文期刊>Cell Reports >Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans
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Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

机译：CAPN1基因的缺陷导致小鼠和人类小脑发育和小脑共济失调的改变

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A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.
机译：帕森罗素梗犬的CAPN1错义突变与脊髓小脑共济失调相关。现在，我们报告人中的纯合子或杂合子CAPN1空突变在四个独立的谱系中导致小脑性共济失调和肢体痉挛。由于异常的小脑发育，钙蛋白酶-1基因敲除（KO）小鼠还表现出轻度共济失调，包括神经元凋亡增加，小脑颗粒细胞数量减少和突触传递改变。凋亡增强是由于缺乏钙蛋白酶1介导的PH结构域和富含亮氨酸的重复蛋白磷酸酶1（PHLPP1）的切割，从而导致发育中的颗粒细胞中Akt的生存前通路受到抑制。向新生小鼠注射间接Akt激活剂，双过氧钒或向calpain-1 KO小鼠注射PHLPP1 KO小鼠可防止成年小鼠出生后小脑颗粒细胞凋亡增加，并恢复颗粒细胞密度和运动协调性。因此，CAPN1突变是包括人类在内的哺乳动物共济失调的另一个原因。

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