SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene

Koht, Jeanette; Stevanin, Giovanni; Dürr, Alexandra; Mundwiller, Emeline; Brice, Alexis; Tallaksen, Chantal

doi:10.1111/j.1600-0404.2011.01504.x

Cited by 16 publications

(22 citation statements)

References 26 publications

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“…Two SCA14 families were identified during an ongoing project on hereditary ataxias in Norway [19,28]. Ten mutation carriers, nine from family 1 and one from family 2 (Table 2), were initially included in the study as affected subjects, independently of clinical signs and symptoms.…”

Section: Methodsmentioning

confidence: 99%

“…DNA was extracted from peripheral blood lymphocytes using standard techniques, and the subjects were identified by direct sequencing of exon 5 in the PRKCG -gene [19]. All healthy related intrafamilial controls were tested for the same mutation.…”

Section: Methodsmentioning

confidence: 99%

“…According to the theory of cerebellar somatotopy [21], cognitive and affective functions have been related to the posterior lobe and vermis especially in the lateral regions of lobule VI and VII (Crus I, Crus II, and VIIB) [6]. Radiologically, cerebellar atrophy is reported in SCA14 patients and is most pronounced in the vermis and posterior lobe [19,22-24], and one could thus expect vulnerability for non-motor symptoms in SCA14 patients.…”

Section: Introductionmentioning

confidence: 99%

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Cognition is only minimally impaired in Spinocerebellar ataxia type 14 (SCA14): a neuropsychological study of ten Norwegian subjects compared to intrafamilial controls and population norm

et al. 2013

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BackgroundThere is an increasing awareness of the role of the cerebellum not only in motor, but also in cognitive and emotional functions. Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant hereditary ataxia characterized by a relatively pure cerebellar phenotype. Cognitive impairment has been reported in studies with phenotype descriptions of SCA14, but previous studies have been small without control groups, and no homogeneous and systematic test panel has been used. The objective of this study was to thoroughly characterize the neuropsychological profile in ten Norwegian SCA14 subjects compared to unaffected family members and population norm data.MethodsTen SCA14 subjects and ten intrafamilial unaffected age- and education-matched controls from two Norwegian families were included. The unaffected intrafamilial controls included six first degree relatives, two second degree relatives, and two spouses. General intellectual ability, memory, visuoperceptive skills, psychomotor speed, executive functions, depression and anxiety were examined using internationally standardized tests, with minimal need for manual response to avoid motor bias.ResultsNo significant cognitive deficit was found in SCA14 subjects compared to intrafamilial controls. Verbal IQ, verbal executive function and psychomotor speed tended to be reduced in affected subjects, but previously reported non-verbal executive dysfunction was not confirmed in this study.ConclusionOnly subtle cognitive impairment was found in SCA14 affected subjects. The current findings do not confirm earlier reports of cognitive dysfunction in SCA14, but does shows a mild impairment in specific verbal executive functions. Genotypic differences may partly account for this discrepancy, and further studies on larger materials are needed to verify the findings.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cognition is only minimally impaired in Spinocerebellar ataxia type 14 (SCA14): a neuropsychological study of ten Norwegian subjects compared to intrafamilial controls and population norm

et al. 2013

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“…Additionally, several mutations in the C2 Ca 2ϩ -binding domain and kinase domain of PKC␥ have been reported ( Fig. 1A) (12,(15)(16)(17)(18)(19)(20). Our previous study showed that Hsp70 (HSPA1A) was incorporated into aggregates of the C1B domain mutants S119P and G128D and that the knockdown of endogenous Hsp70 exacerbated mutant PKC␥-induced cytotoxicity (14).…”

Section: Incorporation and Up-regulation Of Hsp70 Caused By Aggregatimentioning

confidence: 99%

Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14

Nakazono

Adachi

Takahashi

et al. 2018

Journal of Biological Chemistry

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Amyloid and amyloid-like protein aggregations are hallmarks of multiple, varied neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. We previously reported that spinocerebellar ataxia type 14 (SCA14), a dominant-inherited neurodegenerative disease that affects cerebellar Purkinje cells, is characterized by the intracellular formation of neurotoxic amyloid-like aggregates of genetic variants of protein kinase Cγ (PKCγ). A number of protein chaperones, including heat shock protein 70 (Hsp70), promote the degradation and/or refolding of misfolded proteins and thereby prevent their aggregation. Here, we report that, in various SCA14-associated, aggregating PKCγ variants, endogenous Hsp70 is incorporated into aggregates and that expression of these PKCγ mutants up-regulates Hsp70 expression. We observed that PKCγ binds Hsp70 and that this interaction is enhanced in the SCA14-associated variants, mediated by the kinase domain that is involved in amyloid-like fibril formation as well as the C2 domain of PKCγ. Pharmacological up-regulation of Hsp70 by the Hsp90 inhibitors celastrol and herbimycin A attenuated the aggregation of mutant PKCγ in primary cultured Purkinje cells. Up-regulation of Hsp70 diminished net PKCγ aggregation by preventing aggregate formation, resulting in decreased levels of apoptotic cell death among primary cultured Purkinje cells expressing the PKCγ variant. Of note, herbimycin A also ameliorated abnormal dendritic development. Extending our observations, administration of celastrol to mice up-regulated cerebellar Hsp70. Our findings identify heat shock proteins as important endogenous regulators of pathophysiological PKCγ aggregation and point to Hsp90 inhibition as a potential therapeutic strategy in the treatment of SCA14.

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“…The work forms part of a more comprehensive protocol to study the features of spinocerebellar ataxia type 14 (SCA14), a rare hereditary neurodegenerative disorder of adult onset [16]. It is of pure cerebellar phenotype in the majority of cases reported [17]. We therefore consider our results representative for ataxic gait disorder in general.…”

Section: Introductionmentioning

confidence: 96%

Accuracy and repeatability of two methods of gait analysis – GaitRite™ und Mobility Lab™ – in subjects with cerebellar ataxia

et al. 2016

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SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene

Abstract: These are the first families with SCA14 reported from Scandinavia and a new mutation in the PRKCG gene. The occurrence in the Norwegian dominant ataxia cohort is 3.5%.

Cited by 16 publications

References 26 publications

Cognition is only minimally impaired in Spinocerebellar ataxia type 14 (SCA14): a neuropsychological study of ten Norwegian subjects compared to intrafamilial controls and population norm

Cognition is only minimally impaired in Spinocerebellar ataxia type 14 (SCA14): a neuropsychological study of ten Norwegian subjects compared to intrafamilial controls and population norm

Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14

Accuracy and repeatability of two methods of gait analysis – GaitRite™ und Mobility Lab™ – in subjects with cerebellar ataxia

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