Abstract
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.
Highlights
Spinocerebellar ataxias (SCAs) are a group of inherited diseases with mutations in diverse genes, the most common forms are caused by Poly-glutamine repeats in the respective genes
Some forms are caused by point mutations in particular genes, and in Spinocerebellar ataxia type 14 (SCA14) such mutations are found in the PRKCG gene [1], which is coding for protein kinase C gamma (PKCγ) [2]
We have addressed the question whether a similar increase in biological activity of PKCγ might be present in other mutations known to cause SCA14
Summary
Spinocerebellar ataxias (SCAs) are a group of inherited diseases with mutations in diverse genes, the most common forms are caused by Poly-glutamine repeats in the respective genes. The dendritic alterations of Purkinje cells found after PKC activation would be compatible with the hypothesis that pathogenesis of SCA14 might be due at least in part to a gain of function of PKCγ with too strong or constitutive activation of PKC activity This hypothesis is supported by findings that many PKCγ mutations have an increased PKCγ catalytic activity when tested in in vitro or in cell based assays [6, 10, 11]. In Purkinje cells transfected with mutant PKCγ, abnormal dendritic development has been seen irrespective of aggregate formation [15] Taken together, it is still unclear whether the high kinase activity found in cell based assays will eventually lead to increased biologically activity of PKCγ in Purkinje cells and may contribute to the pathogenesis of SCA14
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