Conventional protein kinase C in the brain: repurposing cancer drugs for neurodegenerative treatment?

Lordén, Gema; Newton, Alexandra C.

doi:10.1042/ns20210036

Cited by 16 publications

(10 citation statements)

References 116 publications

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“…For conventional PKC isozymes, loss-of-function somatic mutations or reduced protein levels are associated with cancer (3); in contrast, gain-of-function variants have been identified in neurodegenerative diseases (4)(5)(6). Thus, whereas reduced protein levels and activity of conventional PKC isozymes are associated with poorer patient survival in cancers such as colon and pancreatic cancer, enhanced activity of the conventional PKC is associated with Alzheimer's disease (4,(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…However, it is the unbiased approaches that provide the most compelling evidence for the critical role of PKC in maintaining normal brain function. A comprehensive phosphoproteome analysis by Tagawa et al 29 revealed that PKC substrates account for over half of the core molecules that display increased phosphorylation in AD brains, a finding supported by subsequent phosphoproteomics studies identifying PKC as one of the main kinases activated in AD 30 , and reporting increased phosphorylation of PKCα at Thr638 60 , a quantitatively phosphorylated C-terminal site that serves as an indicator of PKC steady-state levels 61 , 62 . Gain-of-function variants in PKCα segregating with affected family members in LOAD first drew specific attention to this conventional PKC isozyme 21 .…”

Section: Discussionmentioning

confidence: 95%

Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model

et al. 2022

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Exquisitely tuned activity of protein kinase C (PKC) isozymes is essential to maintaining cellular homeostasis. Whereas loss-of-function mutations are generally associated with cancer, gain-of-function variants in one isozyme, PKCα, are associated with Alzheimer’s disease (AD). Here we show that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. This variant causes a modest 30% increase in catalytic activity without altering on/off activation dynamics or stability, underscoring that enhanced catalytic activity is sufficient to drive the biochemical, cellular, and ultimately cognitive effects observed. Analysis of hippocampal neurons from PKCα M489V mice reveals enhanced amyloid-β-induced synaptic depression and reduced spine density compared to wild-type mice. Behavioral studies reveal that this mutation alone is sufficient to impair cognition, and, when coupled to a mouse model of AD, further accelerates cognitive decline. The druggability of protein kinases positions PKCα as a promising therapeutic target in AD.

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“…Mounting evidence points to cancer-associated variants in PKC generally being loss-of-function and variants present in neurodegenerative disease having gain-of-function alterations (39, 64, 65). In this study, we show that mutation of a conserved residue in the C1A domain of cPKC leads to opposing phenotypes depending on the disease context.…”

Section: Discussionmentioning

confidence: 99%

Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration

Jones

Kornev

Weng

et al. 2023

Preprint

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Conventional protein kinase C (PKC) isozymes tune the signaling output of cells, with loss-of-function somatic mutations associated with cancer and gain-of-function germline mutations identified in neurodegeneration. PKC with impaired autoinhibition is removed from the cell by quality-control mechanisms to prevent accumulation of aberrantly active enzyme. Here, we examine how a single residue in the C1A domain of PKCβ, arginine 42 (R42), permits quality-control degradation when mutated to histidine in cancer (R42H) and blocks downregulation when mutated to proline in the neurodegenerative disease spinocerebellar ataxia (R42P). Using FRET-based biosensors, we determined that mutation of R42 to any residue, including lysine, resulted in reduced autoinhibition as indicated by higher basal activity and faster agonist-induced plasma membrane translocation. R42 is predicted to form a stabilizing salt bridge with E655 in the C-tail and mutation of E655, but not neighboring E657, also reduced autoinhibition. Western blot analysis revealed that whereas R42H had reduced stability, the R42P mutant was stable and insensitive to activator-induced ubiquitination and downregulation, an effect previously observed by deletion of the entire C1A domain. Molecular dynamics (MD) simulations and analysis of stable regions of the domain using local spatial pattern (LSP) alignment suggested that P42 interacts with Q66 to impair mobility and conformation of one of the ligand-binding loops. Additional mutation of Q66 to the smaller asparagine (R42P/Q66N), to remove conformational constraints, restored degradation sensitivity to that of WT. Our results unveil how disease-associated mutations of the same residue in the C1A domain can toggle between gain- or loss-of-function of PKC.

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Conventional protein kinase C in the brain: repurposing cancer drugs for neurodegenerative treatment?

Cited by 16 publications

References 116 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

Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model

Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration

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