Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Schmitz‐Hübsch, Tanja; Lux, Silke; Bauer, Péter; Brandt, Alexander U.; Schlapakow, Elena; Greschus, Susanne; Scheel, Michael; Gärtner, Hanna; Kirlangic, Mehmet Eylem; Gras, Vincent; Timmann, Dagmar; Synofzik, Matthis; Giorgetti, Alejandro; Carloni, Paolo; Shah, N. Jon; Schöls, Lüdger; Kopp, Ute A.; Bußenius, Lisa; Oberwahrenbrock, Timm; Zimmermann, Hanna; Pfueller, Caspar F.; Kadas, Ella-Maria; Rönnefarth, Maria; Grosch, Anne-Sophie; Endres, Matthias; Amunts, Katrin; Paul, Friedemann; Doss, Sarah; Minnerop, Martina

doi:10.1002/acn3.51315

Cited by 14 publications

(18 citation statements)

References 63 publications

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“…SCA14 is caused by germline variants in PKC, of which more than 50 unique variants have been identified (Fig. 1A) (25)(26)(27). Although these variants occur in every domain of the kinase, most cluster to the C1 domains, particularly the C1B domain.…”

Section: Previously Undescribed Pkc D115y Is a Pathogenic Variant Fo...mentioning

confidence: 99%

“…Since the original discovery of germline variants in PKC by Raskind and colleagues that defined SCA14 (14,23,24), about 50 variants across all domains of PKC have now been identified in SCA14 (25)(26)(27)(28). Mouse model studies by Kapfhammer and colleagues (29,30) have established that a single SCA14-associated point mutation in PKC is sufficient to drive pathophysiology characteristic of the human disease, including Purkinje cell degeneration and motor deficits.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition

et al. 2022

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Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline variants in the diacylglycerol (DAG)/Ca 2+ -regulated protein kinase Cγ (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. Most of the identified mutations cluster in the DAG-sensing C1 domains. Here, we found with a FRET-based activity reporter that SCA14-associated PKCγ mutations, including a previously undescribed variant, D115Y, enhanced the basal activity of the kinase by compromising its autoinhibition. Unlike other mutations in PKC that impair its autoinhibition but lead to its degradation, the C1 domain mutations protected PKCγ from such down-regulation. This enhanced basal signaling rewired the brain phosphoproteome, as revealed by phosphoproteomic analysis of cerebella from mice expressing a human SCA14-associated H101Y mutant PKCγ transgene. Mutations that induced a high basal activity in vitro were associated with earlier average age of onset in patients. Furthermore, the extent of disrupted autoinhibition, but not agonist-stimulated activity, correlated with disease severity. Molecular modeling indicated that almost all SCA14 variants not within the C1 domain were located at interfaces with the C1B domain, suggesting that mutations in and proximal to the C1B domain are a susceptibility for SCA14 because they uniquely enhance PKCγ basal activity while protecting the enzyme from down-regulation. These results provide insight into how PKCγ activation is modulated and how deregulation of the cerebellar phosphoproteome by SCA14-associated mutations affects disease progression.

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Section: Previously Undescribed Pkc D115y Is a Pathogenic Variant Fo...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition

et al. 2022

View full text Add to dashboard Cite

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“…SCA14 is caused by germline mutations in PKCγ, of which over 50 unique mutations have been identified (Fig. 1A) (22)(23)(24). Although these mutations occur in every domain of the kinase, the majority cluster to the C1 domains, particularly the C1B domain.…”

Section: Pkcγ Mutations Lead To Spinocerebellar Ataxia Type 14mentioning

confidence: 99%

“…Since the original discovery of germline variants in PKCγ by Raskind and colleagues that defined SCA14 (12,20,21), approximately 50 variants across all domains of PKCγ have now been identified in SCA14 (22)(23)(24)(25). Mouse model studies by Kapfhammer and colleagues have established that a single SCA14-associated point mutation in PKCγ is sufficient to drive pathophysiology characteristic of the human disease, including Purkinje cell degeneration and motor deficits (26,27).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase Cγ Mutations Drive Spinocerebellar Ataxia Type 14 by Impairing Autoinhibition

et al. 2021

Preprint

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Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline mutations in the diacylglycerol (DG)/Ca2+-regulated protein kinase C gamma (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. The majority of the approximately 50 mutations identified in PKCγ cluster to the DG-sensing C1 domains. Here, we use a FRET-based activity reporter to show that ataxia-associated PKCγ mutations enhance basal activity by compromising autoinhibition. Although impaired autoinhibition generally leads to PKC degradation, the C1 domain mutations protect PKCγ from phorbol ester-induced downregulation. Furthermore, it is the degree of disrupted autoinhibition, not changes in the amplitude of agonist- stimulated activity, that correlate with disease severity. Specifically, a SCA14 mutation in which phenylalanine 48 in the C1A domain is deleted had high basal activity both in cells and in vitro, yet was unresponsive to agonist stimulation. Validating that the pathology arises from disrupted autoinhibition, we show that the degree of impaired autoinhibition correlates inversely with age of disease onset in patients: mutations that cause high basal activity are associated with early onset, whereas those that only modestly increase basal activity, including a previously undescribed mutation D115Y, are associated with later onset. Molecular modeling indicates that almost all SCA14 mutations that are not in the C1 domains are at interfaces with the C1B domain, and bioinformatics analysis reveals that mutations in the C1B domain are under-represented in cancer. Thus, clustering of SCA14 mutations to the C1B domain provides a unique mechanism to enhance PKCγ basal activity while protecting the enzyme from downregulation.One Sentence SummarySCA14 driver mutations in PKCγ impair autoinhibition, with defect correlating inversely with age of disease onset.

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“…Variants in the gene encoding PKCγ ( PRKCG ) are associated with SCA subtype 14 (SCA14) approximately 20 years ago ( Yamashita et al, 2000 ; Chen et al, 2003 ; Yabe et al, 2003 ). To date, approximately 50 variants in PKCγ have been identified as causative for SCA14, with most mutations occurring in the C1A and C1B domains ( Adachi et al, 2008 ; Wong et al, 2018 ; Shirafuji et al, 2019 ; Schmitz-Hübsch et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration

Pilo

Newton

2022

Front. Cell Dev. Biol.

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Protein kinase C (PKC) isozymes transduce myriad signals within the cell in response to the generation of second messengers from membrane phospholipids. The conventional isozyme PKCγ reversibly binds Ca2+ and diacylglycerol, which leads to an open, active conformation. PKCγ expression is typically restricted to neurons, but evidence for its expression in certain cancers has emerged. PKC isozymes have been labeled as oncogenes since the discovery that they bind tumor-promoting phorbol esters, however, studies of cancer-associated PKC mutations and clinical trial data showing that PKC inhibitors have worsened patient survival have reframed PKC as a tumor suppressor. Aberrant expression of PKCγ in certain cancers suggests a role outside the brain, although whether PKCγ also acts as a tumor suppressor remains to be established. On the other hand, PKCγ variants associated with spinocerebellar ataxia type 14 (SCA14), a neurodegenerative disorder characterized by Purkinje cell degeneration, enhance basal activity while preventing phorbol ester-mediated degradation. Although the basis for SCA14 Purkinje cell degeneration remains unknown, studies have revealed how altered PKCγ activity rewires cerebellar signaling to drive SCA14. Importantly, enhanced basal activity of SCA14-associated mutants inversely correlates with age of onset, supporting that enhanced PKCγ activity drives SCA14. Thus, PKCγ activity should likely be inhibited in SCA14, whereas restoring PKC activity should be the goal in cancer therapies. This review describes how PKCγ activity can be lost or gained in disease and the overarching need for a PKC structure as a powerful tool to predict the effect of PKCγ mutations in disease.

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Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Cited by 14 publications

References 63 publications

Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition

Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition

Protein Kinase Cγ Mutations Drive Spinocerebellar Ataxia Type 14 by Impairing Autoinhibition

Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration

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