Spinocerebellar ataxia 14: Novel mutation in exon 2 of <i>PRKCG</i> in a German family

Nolte, Dagmar; Landendinger, Melanie; Schmitt, Eberhard; Müller, Ulrich

doi:10.1002/mds.21269

Cited by 18 publications

(11 citation statements)

References 14 publications

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“…Missense mutations in the PRKCG gene encoding protein kinase Cc (cPKC) have been identified as a cause of SCA14 . To date, 23 mutations have been identified in different SCA14 families, including a 2-amino acid-deletion mutant (DK100-H101) (van de Warrenburg et al 2003;Yabe et al 2003;Stevanin et al 2004;Alonso et al 2005;Chen et al 2005;Klebe et al 2005Klebe et al , 2007Verbeek et al 2005a,b;Dalski et al 2006;Hiramoto et al 2006;Vlak et al 2006;Nolte et al 2007;Wieczorek et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy

Yamamoto¹,

Seki²,

Adachi³

et al. 2010

Genes to Cells

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Several causal missense mutations in the protein kinase Cc (cPKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously showed that mutant cPKC found in SCA14 is susceptible to aggregation and causes apoptosis. Aggregation of misfolded proteins is generally involved in the pathogenesis of many neurodegenerative diseases. Growing evidence indicates that macroautophagy (autophagy) is important for the degradation of misfolded proteins and the prevention of neurodegenerative diseases. In the present study, we examined whether autophagy is involved in the degradation of the mutant cPKC that causes SCA14. Mutant cPKC-GFP was transiently expressed in SH-SY5Y cells by using an adenoviral tetracycline-regulated system. Subsequently, temporal changes in clearance of aggregates and degradation of cPKC-GFP were evaluated. Rapamycin, an autophagic inducer, accelerated clearance of aggregates and promoted degradation of mutant cPKC-GFP, but it did not affect degradation of wild-type cPKC-GFP. These effects of rapamycin were not observed in embryonic fibroblast cells from Atg5-deficient mice, which are not able to perform autophagy. Furthermore, lithium, another type of autophagic inducer, also promoted the clearance of mutant cPKC aggregates. These results indicate that autophagy contributes to the degradation of mutant cPKC, suggesting that autophagic inducers could provide therapeutic potential for SCA14.

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Section: Introductionmentioning

confidence: 99%

Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy

Yamamoto¹,

Seki²,

Adachi³

et al. 2010

Genes to Cells

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“…To date, 22 different PKC␥ mutations have been found in SCA14 families, 18 of which map to the C1 domain (11)(12)(13)(14)(15)(16). This fact strongly suggests that these mutations disturb a fundamental property of PKC␥ including membrane translocation and activator-dependent regulation of its kinase activity.…”

mentioning

confidence: 99%

Enzymological Analysis of Mutant Protein Kinase Cγ Causing Spinocerebellar Ataxia Type 14 and Dysfunction in Ca2+ Homeostasis

Adachi

Kobayashi

Takahashi

et al. 2008

Journal of Biological Chemistry

133

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Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in protein kinase C␥ (PKC␥). Interestingly, 18 of 22 mutations are concentrated in the C1 domain, which binds diacylglycerol and is necessary for translocation and regulation of PKC␥ kinase activity. To determine the effect of these mutations on PKC␥ function and the pathology of SCA14, we investigated the enzymological properties of the mutant PKC␥s. We found that wild-type PKC␥, but not C1 domain mutants, inhibits Ca 2؉ influx in response to muscarinic receptor stimulation. The sustained Ca 2؉ influx induced by muscarinic receptor ligation caused prolonged membrane localization of mutant PKC␥. Pharmacological experiments showed that canonical transient receptor potential (TRPC) channels are responsible for the Ca 2؉ influx regulated by PKC␥. Although in vitro kinase assays revealed that most C1 domain mutants are constitutively active, they could not phosphorylate TRPC3 channels in vivo. Single molecule observation by the total internal reflection fluorescence microscopy revealed that the membrane residence time of mutant PKC␥s was significantly shorter than that of the wild-type. This fact indicated that, although membrane association of the C1 domain mutants was apparently prolonged, these mutants have a reduced ability to bind diacylglycerol and be retained on the plasma membrane. As a result, they fail to phosphorylate TRPC channels, resulting in sustained Ca 2؉ entry. Such an alteration in Ca 2؉ homeostasis and Ca 2؉ -mediated signaling in Purkinje cells may contribute to the neurodegeneration characteristic of SCA14.Autosomal dominant SCA14 is a genetically heterogenous group of neurodegenerative disorders characterized by progressive motor incoordination affecting the gait and limbs, cerebellar dysarthria, and nystagmus due to degeneration of cerebellar Purkinje cells. SCA14 is caused by missense or in-frame deletion mutations in the PRKCG gene encoding protein kinase C␥ (PKC␥) 2 (1). PKC␥ is a member of the PKC family that plays critical roles in many cellular functions, affecting diverse signal transduction pathways (2). PKC␥ is selectively expressed in neurons throughout the brain and is most abundant in cerebellar Purkinje cells (3), which specifically degenerate in SCA14 patients.One of the characteristic features of PKC␥ is its translocation from the cytoplasm to the plasma membrane (4). Translocation is a hallmark of enzyme activation and is triggered by the stimulation of G protein-coupled receptors. It is well known that activation of such receptors causes elevations of DAG and intracellular Ca 2ϩ (5). PKC␥ contains C1 and C2 domains in its regulatory domain (6). The C1 domain has two zinc-finger motifs, C1A and C1B, that contain highly conserved Cys residues that bind to diacylglycerol (DAG) and tumor promoting phorbol esters. The C2 domain is a Ca 2ϩ sensor that binds phosphatidylserine (PS) in the presence of elevated Ca 2ϩ . The C1 and C2 domains play crucial roles in PKC␥ transloca...

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“…Twelve mutations are clustered in exon 4, the remaining ones are located in exons 1, 2, 5, 10, and 18 of PRKCG. 5 Here we describe a mutation in exon 4 of PRKCG in a patient from a small German SCA14 family. The index case (III/1 of Fig.…”

Section: Codon 101 Of Prkcg a Preferential Mutation Site In Sca14mentioning

confidence: 90%