Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia
Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia
复制标题
蛋白激酶C活性是小脑性共济失调中浦肯野神经元变性的一种保护性调节因子
DOI：
10.1093/hmg/ddy050
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发表时间：
2018-04-15
影响因子：
3.5
通讯作者：
Shakkottai, Vikram G.
中科院分区：
文献类型：
--
作者：
Chopra, Ravi;Wasserman, Aaron H.;Shakkottai, Vikram G.
在表达蛋白激酶C（PKC）酶的许多类型的神经元中，小脑浦肯野神经元特别依赖于适当的PKC活性来维持稳态。PKC酶在浦肯野神经元健康中的重要性是显而易见的，因为PRKCG（编码PKC c）的突变引起小脑共济失调。PRKCG也已被确定为共济失调基因网络中的一个重要节点，但PKC在其他形式的共济失调中的功能作用仍未被探索，PKC同工酶调节浦肯野神经元健康的机制也不清楚。在这里，我们研究了PKC活性如何影响遗传性共济失调的神经变性。使用脊髓小脑性共济失调1型（SCA1）和2型（SCA2）小鼠模型，我们确定了两种不同形式的遗传性小脑性共济失调中PKC介导的底物磷酸化的增加。SCA1和SCA2小鼠中正常化PKC底物磷酸化加速变性，表明在这些模型中观察到的活性增加具有神经保护作用。我们还发现，增加磷酸化的PKC目标限制浦肯野神经元膜的兴奋性，这表明PKC活性可能支持浦肯野神经元的健康，通过调节兴奋性。这些数据表明PKC酶在共济失调基因网络中的功能作用，并证明PKC活性增加是遗传性小脑共济失调变性的保护性修饰剂。
Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCc) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood. Here, we investigated how PKC activity influences neurodegeneration in inherited ataxia. Using mouse models of spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) we identify an increase in PKC-mediated substrate phosphorylation in two different forms of inherited cerebellar ataxia. Normalizing PKC substrate phosphorylation in SCA1 and SCA2 mice accelerates degeneration, suggesting that the increased activity observed in these models is neuroprotective. We also find that increased phosphorylation of PKC targets limits Purkinje neuron membrane excitability, suggesting that PKC activity may support Purkinje neuron health by moderating excitability. These data suggest a functional role for PKC enzymes in ataxia gene networks, and demonstrate that increased PKC activity is a protective modifier of degeneration in inherited cerebellar ataxia.