Anatomical Institute, Department of Biomedicine Basel, University of Basel, Pestalozzistrasse 20, 4056, Basel, Switzerland.
Mol Brain. 2017 Jul 24;10(1):34. doi: 10.1186/s13041-017-0313-z.
Spinocerebellar ataxia (SCA) is an autosomal dominant neurodegenerative disorder characterized by slowly progressive cerebellar dysfunction. Currently, 42 SCA types are known, some of which are caused by CAG repeat expansions, but others are caused by point mutations or deletions. Spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations or deletions in the PRKCG gene, coding for protein kinase C gamma (PKCγ). It is still not well understood how these mutations eventually cause Purkinje cell dysfunction and death. Because PKCγ is a well characterized signaling protein highly expressed in Purkinje cells SCA14 offers the chance to better understand the pathogenesis of Purkinje cell dysfunction and death. Altered biological activity of PKCγ would be the simplest explanation for the disease phenotype. There are indeed indications that the enzymatic activity of mutated PKCγ proteins could be changed. Many mutations found in SCA14 families are located in the regulatory C1B and C1A domain, while a few mutations are also found in the C2 and in the catalytic C3 and C4 domains. For many of these mutations an increased enzymatic activity could be demonstrated in cell-based assays, but it remains unclear whether there is indeed an altered biological activity of the mutated PKCγ proteins within living Purkinje cells. In this study we used the dendritic morphology of developing Purkinje cells to detect increased biological activity of PKCγ after expression of different mutated PKCγ proteins. Our results indicate that two out of three known mutations in the catalytic domain of PKCγ did indeed show increased biological activity. On the other hand, none of the five tested mutations located in the regulatory C1 or the C2 domain showed an increased biological activity. Our findings indicate that SCA14 mutations located in different domains of the PRKCG gene cause SCA14 by different mechanisms and that an increased constitutive activity of PKCγ may be one, but cannot be the only mechanism to cause disease in SCA14.
脊髓小脑共济失调（SCA）是一种常染色体显性遗传性神经退行性疾病，其特征是小脑功能进行性缓慢恶化。目前已知有 42 种 SCA 类型，其中一些是由 CAG 重复扩展引起的，而另一些是由点突变或缺失引起的。脊髓小脑共济失调 14 型（SCA14）是由 PRKCG 基因中的错义突变或缺失引起的，该基因编码蛋白激酶 C 伽马（PKCγ）。目前尚不清楚这些突变最终如何导致浦肯野细胞功能障碍和死亡。由于 PKCγ 是一种在浦肯野细胞中高度表达的特征明确的信号蛋白，因此 SCA14 为更好地理解浦肯野细胞功能障碍和死亡的发病机制提供了机会。PKCγ 的生物学活性改变将是对疾病表型的最简单解释。实际上有迹象表明，突变的 PKCγ 蛋白的酶活性可能发生改变。在 SCA14 家族中发现的许多突变位于调节 C1B 和 C1A 结构域，而少数突变也位于 C2 结构域以及催化 C3 和 C4 结构域。在许多此类突变中，在基于细胞的测定中可以证明酶活性增加，但尚不清楚在活的浦肯野细胞中突变的 PKCγ 蛋白是否确实具有改变的生物学活性。在这项研究中，我们使用发育中的浦肯野细胞的树突形态来检测表达不同突变的 PKCγ 后 PKCγ 的生物学活性增加。我们的结果表明，PKCγ 催化结构域中的三个已知突变中的两个确实显示出增加的生物学活性。另一方面，位于调节 C1 或 C2 结构域的五个测试突变均未显示出增加的生物学活性。我们的研究结果表明，PRKCG 基因不同结构域中的 SCA14 突变通过不同的机制引起 SCA14，并且 PKCγ 的组成型活性增加可能是一种但不是唯一导致 SCA14 疾病的机制。
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