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Sex specific disruptions in PKCγ signaling in a mouse model of Spinocerebellar Ataxia Type 14

ABSTRACT: Spinocerebellar Ataxia Type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene-encoding protein kinase C gamma (PKCγ), a Ca2+/diacylglycerol (DG)-dependent serine/threonine kinase dominantly expressed in the Purkinje cells of the cerebellum, a brain region that regulates motor function. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in dysregulated cerebellar function. To better understand the phenotypic impact of aberrant PKCγ signaling in disease pathology, we developed a knock-in murine model of the SCA14 mutation ΔF48 in PKCγ. This fully penetrant mutation is one of the most severe in humans, with the age of disease onset in early childhood. Genetic, behavioral, and molecular testing revealed that ΔF48 PKCγ SCA14 mice have sex-specific, ataxia related phenotypes, and that ΔF48 PKCγ distinctly alters the cerebellar phosphoproteome in SCA14 male and female mice. Analysis of existing human data reveal that SCA14 has a significantly earlier age of onset for males compared with females. Our data reveal that sex-specific differences in SCA14 pathology arise from the clinically relevant ΔF48 PKCγ mutation and suggest that treatment strategies to modulate aberrant PKCγ may be particularly beneficial in males.

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ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Majid Ghassemian

LAB HEAD: Alexandra C. Newton1

PROVIDER: PXD060630 | Pride | 2026-03-16

REPOSITORIES: Pride

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Project description:Microglia, the brain’s principal immune cells, have been implicated in the pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic findings. There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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Sex specific disruptions in PKCγ signaling in a mouse model of Spinocerebellar Ataxia Type 14

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