Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation

Wong, Maggie M. K.; Hoekstra, Stephanie D.; Vowles, Jane; Watson, Lauren M.; Fuller, Geraint; Németh, Andrea H.; Cowley, Sally A.; Ansorge, Olaf; Talbot, Kevin; Becker, Esther B. E.

doi:10.1186/s40478-018-0600-7

Cited by 39 publications

(72 citation statements)

References 46 publications

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“…There are now >40 different missense mutations or deletions which have been found in human SCA14 patients ( Chelban et al, 2018 ; Wong et al, 2018 ) ( Fig. 1 A ).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, other SCA14 mutations, especially in the C1 domain, are functionally defective because of decreased binding to diacylglycerol pointing toward a loss of function phenotype ( Verbeek et al, 2008 ). These findings suggest that pathology in SCA14 is not simply because of one single mechanism but rather the result of complex mechanisms involving dysregulation of PKCγ ( Shimobayashi and Kapfhammer, 2018 ; Wong et al, 2018 ).…”

Section: Introductionmentioning

confidence: 94%

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A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

Shimobayashi

Kapfhammer

2021

J. Neurosci.

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Spinocerebellar ataxias (SCAs) are diseases characterized by cerebellar atrophy and loss of Purkinje neurons caused by mutations in diverse genes. In SCA14, the disease is caused by point mutations or small deletions in protein kinase C γ (PKCγ), a crucial signaling protein in Purkinje cells. It is still unclear whether increased or decreased PKCγ activity may be involved in the SCA14 pathogenesis. In this study, we present a new knock-in mouse model related to SCA14 with a point mutation in the pseudosubstrate domain, PKCγ-A24E, known to induce a constitutive PKCγ activation. In this protein conformation, the kinase domain of PKCγ is activated, but at the same time the protein is subject to dephosphorylation and protein degradation. As a result, we find a dramatic reduction of PKCγ protein expression in PKC γ -A24E mice of either sex. Despite this reduction, there is clear evidence for an increased PKC activity in Purkinje cells from PKC γ -A24E mice. Purkinje cells derived from PKCγ-A24E have short thickened dendrites typical for PKC activation. These mice also develop a marked ataxia and signs of Purkinje cell dysfunction making them an interesting new mouse model related to SCA. Recently, a similar mutation in a human patient was discovered and found to be associated with overt SCA14. RNA profiling of PKC γ -A24E mice showed a dysregulation of related signaling pathways, such as mGluR1 or mTOR. Our results show that the induction of PKCγ activation in Purkinje cells results in the SCA-like phenotype indicating PKC activation as one pathogenetic avenue leading to a SCA. SIGNIFICANCE STATEMENT Spinocerebellar ataxias (SCAs) are hereditary diseases affecting cerebellar Purkinje cells and are a one of neurodegenerative diseases. While mutation in several genes have been identified as causing SCAs, it is unclear how these mutations cause the disease phenotype. Mutations in PKCγ cause one subtype of SCAs, SCA14. In this study, we have generated a knock-in mouse with a mutation in the pseudosubstrate domain of PKCγ, which keeps PKCγ in the constitutive active open conformation. We show that this mutation leading to a constant activation of PKCγ results in a SCA-like phenotype in these mice. Our findings establish the constant activation of PKC signaling as one pathogenetic avenue leading to an SCA phenotype and a mechanism causing a neurodegenerative disease.

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“…There are now >40 different missense mutations or deletions which have been found in human SCA14 patients ( Chelban et al, 2018 ; Wong et al, 2018 ) ( Fig. 1 A ).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

Shimobayashi

Kapfhammer

2021

J. Neurosci.

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“…The rapid development in the iPSC field and the potential of iPSC to differentiate into different cell types not only offer great opportunities to study the pathogenesis of neurodegenerative diseases including SCA3 but also provide a platform to identify new therapeutic strategies [28–31]. In the past decade, neuronal cells derived from patient-specific iPSCs have been generated to model neurodegenerative diseases such as PD [32, 33], Alzheimer's disease (AD) [34, 35], and HD [36, 37], and relatively handful iPSC studies focused on cerebellar ataxias including Friedreich's ataxia (FRDA) [38–43] and SCAs: SCA2 [44], SCA3 [45–48], SCA6 [49], SCA7 [50], SCA14 [51], and SCA36 [52]. Koch et al first reported that L-glutamate-induced excitation of SCA3-iPSC-derived neurons initiated calpain-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates [46].…”

Section: Discussionmentioning

confidence: 99%

Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

Chen

Chang

Chen

et al. 2019

Oxidative Medicine and Cellular Longevity

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Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ATXN3/MJD1 gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from Pueraria lobata) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.

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“…The abnormal increase in sustained cytosolic Ca 2+ by TRPC5 activation causes neuronal damage through the calpain-caspase-dependent pathway and the CaM kinase as seen in HD (Hong et al, 2015 ). Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant ND caused by a mutation in protein kinase Cγ (Wong et al, 2018 ). This mutation of SCA14 has been demonstrated to cause phosphorylation failure in TRPC3 channels, resulting in persistent Ca 2+ entry that may contribute to neurodegeneration (Adachi et al, 2008 ).…”

Section: Brain Disordersmentioning

confidence: 99%

The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis

Hwang

Lee

Kim

2021

Front. Cell Dev. Biol.

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Brain disorders include neurodegenerative diseases (NDs) with different conditions that primarily affect the neurons and glia in the brain. However, the risk factors and pathophysiological mechanisms of NDs have not been fully elucidated. Homeostasis of intracellular Ca2+ concentration and intracellular pH (pHi) is crucial for cell function. The regulatory processes of these ionic mechanisms may be absent or excessive in pathological conditions, leading to a loss of cell death in distinct regions of ND patients. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where disrupted Ca2+ homeostasis leads to cell death. The capability of TRP channels to restore or excite the cell through Ca2+ regulation depending on the level of plasma membrane Ca2+ ATPase (PMCA) activity is discussed in detail. As PMCA simultaneously affects intracellular Ca2+ regulation as well as pHi, TRP channels and PMCA thus play vital roles in modulating ionic homeostasis in various cell types or specific regions of the brain where the TRP channels and PMCA are expressed. For this reason, the dysfunction of TRP channels and/or PMCA under pathological conditions disrupts neuronal homeostasis due to abnormal Ca2+ and pH levels in the brain, resulting in various NDs. This review addresses the function of TRP channels and PMCA in controlling intracellular Ca2+ and pH, which may provide novel targets for treating NDs.

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Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation

Cited by 39 publications

References 46 publications

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

A New Mouse Model Related to SCA14 Carrying a Pseudosubstrate Domain Mutation in PKCγ Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior

Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis

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