Sex-specific disruptions in PKCγ signaling in a mouse model of spinocerebellar ataxia type 14

JCI Insight · 2026-04-02

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene encoding protein kinase C γ (PKCγ), a Ca2+- and diacylglycerol-dependent Ser/Thr kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. To better understand the impact of aberrant PKCγ signaling in disease pathology, we developed a knockin murine model of the SCA14 mutation ΔF48 in PKCγ. This fully penetrant mutation is severe in humans and is mechanistically informative, as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that ΔF48 PKCγ mice have ataxia-related phenotypes and an altered cerebellar phosphoproteome driven primarily by enhanced Ca2+/calmodulin-dependent kinase 2 signaling, effects that were more severe in male mice. Analysis of existing human data revealed that SCA14 has a significantly earlier age of onset for males compared with females. Data from this clinically relevant mutation suggested that enhanced basal activity of PKCγ is sufficient to cause ataxia and that treatment strategies to modulate aberrant PKCγ may be particularly beneficial in males.

A PKCη missense mutation enhances Golgi-localized signaling and is associated with recessively inherited familial Alzheimer’s disease

Science Signaling · 2025-07-01 · 2 citations

The identification of Alzheimer’s disease (AD)–associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWASs) of AD have successfully identified previously unidentified targets but have almost exclusively used additive genetic models. Here, we performed a family-based GWAS of a recessive inheritance model using whole-genome sequencing from families affected by AD. We found an association between AD risk and the variant rs7161410, which is located in an intron of the PRKCH gene encoding protein kinase C eta (PKCη). In addition, a rare PRKCH missense mutation, K65R, was in linkage disequilibrium with rs7161410 and was present in homozygous carriers of the rs7161410 risk allele. In vitro analysis revealed that the catalytic rate, lipid dependence, and peptide substrate binding of the purified variant were indistinguishable from those of the wild-type kinase. However, cellular studies revealed that the K65R PKCη variant had reduced cytosolic activity and, instead, enhanced localization and signaling at the Golgi. Moreover, the K65R variant had altered interaction networks in transfected cells, particularly with proteins involved in Golgi processes such as vesicle transport. In human brain tissue, the AD-associated recessive genotype of rs7161410 was associated with increased expression of PRKCH , particularly in the amygdala. This association of aberrant PKCη signaling with AD and the insight into how its function is altered may lead to previously unidentified therapeutic targets for prevention and treatment.

Sex specific disruptions in Protein Kinase Cγ signaling in a mouse model of Spinocerebellar Ataxia Type 14

bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-11

/diacylglycerol (DG)-dependent serine/threonine kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. 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 severe in humans and is mechanistically informative as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that ΔF48 PKCγ SCA14 mice have ataxia related phenotypes and an altered cerebellar phosphoproteome, effects that are more severe in male mice. Analysis of existing human data reveal that SCA14 has a significantly earlier age of onset for males compared with females. Our data from this clinically relevant mutation suggest that enhanced basal activity of PKCγ is necessary and sufficient to cause ataxia and that treatment strategies to modulate aberrant PKCγ may be particularly beneficial in males. Summary: New mouse model of Spinocerebellar Ataxia Type 14 containing a clinically relevant mutation in PKCγ identified underlying drivers of the disease and neuroprotection in females.

Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer’s disease using a recessive mode of inheritance

medRxiv · 2025-05-14 · 1 citations

Abstract The identification of Alzheimer’s disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWAS) for AD have successfully identified new targets but have almost exclusively utilized additive genetic models. Here, we performed a family-based GWAS under a recessive inheritance model using whole genome sequencing from families affected by AD. We found that the variant, rs7161410, located in an intron of the PRKCH gene, encoding protein kinase C eta (PKCη), was associated with AD risk (p-value=1.41 × 10−7). Further analysis revealed a rare PRKCH missense mutation K65R in linkage disequilibrium with rs7161410, which was present in homozygous carriers of the rs7161410 risk allele. We show that this mutation leads to enhanced localization and signaling of PKCη at the Golgi. The novel genetically-validated association of aberrant PKCη signaling with AD opens avenues for new therapeutic targets aimed at prevention and treatment. One Sentence Summary Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer’s disease.

Investigating The Effects of The Menstrual Cycle on Glycogen Utilisation and Metabolic Activity During Exercise: A 13C MRS Study

Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2024-11-26

Motivation: The menstrual cycle (MC) has been shown to effect muscle glycogen utilisation during exercise but little is known about the full metabolic or glycogenic effects at varying phases. Goal(s): To explore MC effects on exercise-induced changes in metabolites and glycogen stores. Approach: 13C MRS and bloods were acquired from the liver and leg before and after 45 minutes of moderate exercise in healthy females. Test day was repeated 4 times 1 week apart throughout the MC. Results: Previous findings of hormonal effects on muscle glycogen utilization were confirmed. Also, liver glycogen stores appear reduced in later MC days and correlated negatively with progesterone. Impact: This study provides pilot data for future research. 13C MRS allows for the repeated monitoring of glycogen storage and turnover in an ethically viable way. This work has implications in understanding metabolic disorders, medical research and sports science.

Alcohol dependence interactions with sex-specific stress-related neuropeptide and alcohol CeA synaptic effects

Alcohol · 2023-05-09

Alcohol Dependence Induces CRF Sensitivity in Female Central Amygdala GABA Synapses

International Journal of Molecular Sciences · 2022-07-16 · 24 citations

Alcohol use disorder (AUD) is a chronically relapsing disease characterized by loss of control in seeking and consuming alcohol (ethanol) driven by the recruitment of brain stress systems. However, AUD differs among the sexes: men are more likely to develop AUD, but women progress from casual to binge drinking and heavy alcohol use more quickly. The central amygdala (CeA) is a hub of stress and anxiety, with corticotropin-releasing factor (CRF)-CRF1 receptor and Gamma-Aminobutyric Acid (GABA)-ergic signaling dysregulation occurring in alcohol-dependent male rodents. However, we recently showed that GABAergic synapses in female rats are less sensitive to the acute effects of ethanol. Here, we used patch-clamp electrophysiology to examine the effects of alcohol dependence on the CRF modulation of rat CeA GABAergic transmission of both sexes. We found that GABAergic synapses of naïve female rats were unresponsive to CRF application compared to males, although alcohol dependence induced a similar CRF responsivity in both sexes. In situ hybridization revealed that females had fewer CeA neurons containing mRNA for the CRF1 receptor (Crhr1) than males, but in dependence, the percentage of Crhr1-expressing neurons in females increased, unlike in males. Overall, our data provide evidence for sexually dimorphic CeA CRF system effects on GABAergic synapses in dependence.

Proliferation of steatocystomas in 2 transgender men

JAAD Case Reports · 2022-07-02 · 1 citations

Exogenous testosterone is often used by transgender men for virilization and to suppress feminizing attributes. Although there are physical features of testosterone that are desired for men who are transitioning, such as deepening of the voice and facial hair development, it may also result in unwanted cutaneous side effects. Although androgen receptors within the pilosebaceous unit function to increase the facial and body hair, which improves gender dysphoria, anxiety, and depression, the impact of testosterone on these receptors can contribute to undesired changes, including scalp hair loss and acne exacerbation following increased sebum production.

The Synaptic Interactions of Alcohol and the Endogenous Cannabinoid System

Alcohol research · 2022-01-01 · 30 citations

PURPOSE: A growing body of evidence has implicated the endocannabinoid (eCB) system in the acute, chronic, and withdrawal effects of alcohol/ethanol on synaptic function. These eCB-mediated synaptic effects may contribute to the development of alcohol use disorder (AUD). Alcohol exposure causes neurobiological alterations similar to those elicited by chronic cannabinoid (CB) exposure. Like alcohol, cannabinoids alter many central processes, such as cognition, locomotion, synaptic transmission, and neurotransmitter release. There is a strong need to elucidate the effects of ethanol on the eCB system in different brain regions to understand the role of eCB signaling in AUD. SEARCH METHODS: For the scope of this review, preclinical studies were identified through queries of the PubMed database. SEARCH RESULTS: This search yielded 459 articles. Clinical studies and papers irrelevant to the topic of this review were excluded. DISCUSSION AND CONCLUSIONS: . These alcohol-induced alterations of the eCB system have subsequent effects on synaptic function including neuronal excitability and postsynaptic conductance. This review will provide a comprehensive evaluation of the current literature on the synaptic interactions of alcohol exposure and eCB signaling systems, with an emphasis on molecular and physiological synaptic effects of alcohol on the eCB system. A limited volume of studies has focused on the underlying interactions of alcohol and the eCB system at the synaptic level in the brain. Thus, the data on synaptic interactions are sparse, and future research addressing these interactions is much needed.

Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor 1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

Molecular Psychiatry · 2022-06-06 · 34 citations

Abstract Prefrontal circuits are thought to underlie aberrant emotion contributing to relapse in abstinence; however, the discrete cell-types and mechanisms remain largely unknown. Corticotropin-releasing factor and its cognate type-1 receptor, a prominent brain stress system, is implicated in anxiety and alcohol use disorder (AUD). Here, we tested the hypothesis that medial prefrontal cortex CRF1-expressing (mPFC CRF1+ ) neurons comprise a distinct population that exhibits neuroadaptations following withdrawal from chronic ethanol underlying AUD-related behavior. We found that mPFC CRF1+ neurons comprise a glutamatergic population with distinct electrophysiological properties and regulate anxiety and conditioned rewarding effects of ethanol. Notably, mPFC CRF1+ neurons undergo unique neuroadaptations compared to neighboring neurons including a remarkable decrease in excitability and glutamatergic signaling selectively in withdrawal, which is driven in part by the basolateral amygdala. To gain mechanistic insight into these electrophysiological adaptations, we sequenced the transcriptome of mPFC CRF1+ neurons and found that withdrawal leads to an increase in colony-stimulating factor 1 (CSF1) in this population. We found that selective overexpression of CSF1 in mPFC CRF1+ neurons is sufficient to decrease glutamate transmission, heighten anxiety, and abolish ethanol reinforcement, providing mechanistic insight into the observed mPFC CRF1+ synaptic adaptations in withdrawal that drive these behavioral phenotypes. Together, these findings highlight mPFC CRF1+ neurons as a critical site of enduring adaptations that may contribute to the persistent vulnerability to ethanol misuse in abstinence, and CSF1 as a novel target for therapeutic intervention for withdrawal-related negative affect.