<scp>RGS14</scp> expression in <scp>CA2</scp> hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease

Montañez-Miranda, Carolina; Bramlett, Sara N; Hepler, John R.

doi:10.1002/hipo.23492

Cited by 7 publications

(6 citation statements)

References 167 publications

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“…Antibodies raised against several different proteins are now known to reliably label CA2 in mice (Radzicki et al, 2023). In fact, antibodies against RGS14 label CA2 in a number of species including mice and rats and human and nonhuman primates ((Alexander et al, 2016; Lee et al, 2010), and Montanez‐Miranda et al, 2022). Mouse monoclonal antibodies against RGS14, however, showed no evidence of labeling CA2 or elsewhere in the fox hippocampus (not shown).…”

Section: Resultsmentioning

confidence: 99%

Defining hippocampal area CA2 in the fox (Vulpes vulpes) brain

et al. 2023

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Since 1959, the Russian Farm-Fox study has bred foxes to be either tame or, more recently, aggressive, and scientists have used them to gain insight into the brain structures associated with these behavioral features. In mice, hippocampal area CA2 has emerged as one of the essential regulators of social aggression, and so to eventually determine whether we could identify differences in CA2 between tame and aggressive foxes, we first sought to identify CA2 in foxes (Vulpes vulpes). As no clearly defined area of CA2 has been described in species such as cats, dogs, or pigs, it was not at all clear whether CA2 could be identified in foxes. In this study, we cut sections of temporal lobes from male and female red foxes, perpendicular to the long axis of the hippocampus, and stained them with markers of CA2 pyramidal cells commonly used in tissue from rats and mice. We observed that antibodies against Purkinje cell protein 4 best stained the pyramidal cells in the area spanning the end of the mossy fibers and the beginning of the pyramidal cells lacking mossy fibers, resembling the pattern seen in rats and mice. Our findings indicate that foxes do have a "molecularly defined" CA2, and further, they suggest that other carnivores like dogs and cats might as well. With this being the case, these foxes could be useful in future studies looking at CA2 as it relates to aggression.

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Section: Resultsmentioning

confidence: 99%

Defining hippocampal area CA2 in the fox (Vulpes vulpes) brain

et al. 2023

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“…Our analysis has identified DMPs that have not been described previously, potentially due to the use of the Infinium MethylationEPIC array, which interrogates nearly twice as many CpGs compared to the previous Illumina 450K array. Notably, significant DMPs were found near the RGS14 gene, which is implicated in regulating synaptic plasticity in neurons 28,29 . Interestingly, a decrease in RGS14 protein expression has been noted in the putamen of PD patients 30 .…”

Section: Discussionmentioning

confidence: 98%

“…Notably, significant DMPs were found near the RGS14 gene, which is implicated in regulating synaptic plasticity in neurons. 28,29 Interestingly, a decrease in RGS14 protein expression has been noted in the putamen of PD patients. 30 Additionally, the VPS28 gene that exhibited significant differences between groups belongs to the VPS family of proteins that are thought to mitigate alpha-synuclein toxicity by regulating protein sorting within the Golgi complex.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Blood Methylome as Potential Epigenetic Biomarker in Sporadic Parkinson's Disease

Gonzalez‐Latapi,

Bustos,

Dong

et al. 2024

Annals of Neurology

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ObjectiveTo characterize DNA methylation (DNAm) differences between sporadic Parkinson's disease (PD) and healthy control (HC) individuals enrolled in the Parkinson's Progression Markers Initiative (PPMI).MethodsUsing whole blood, we characterized longitudinal differences in DNAm between sporadic PD patients (n = 196) and HCs (n = 86) enrolled in PPMI. RNA sequencing (RNAseq) was used to conduct gene expression analyses for genes mapped to differentially methylated cytosine‐guanine sites (CpGs).ResultsAt the time of patient enrollment, 5,178 CpGs were differentially methylated (2,683 hypermethylated and 2,495 hypomethylated) in PD compared to HC. Of these, 579 CpGs underwent significant methylation changes over 3 years. Several differentially methylated CpGs were found near the cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene. Additionally, multiple hypermethylated CpGs were associated with the N‐myc downregulated gene family member 4 (NDRG4) gene. RNA‐Seq analyses showed 75 differentially expressed genes in PD patients compared to controls. An integrative analysis of both differentially methylated sites and differentially expressed genes revealed 20 genes that exhibited hypomethylation concomitant with overexpression. Additionally, 1 gene, cathepsin H (CTSH), displayed hypermethylation that was associated with its decreased expression.InterpretationWe provide initial evidence of alterations in DNAm in blood of PD patients that may serve as potential epigenetic biomarker of disease. To evaluate the significance of these changes throughout the progression of PD, additional profiling at longer intervals and during the prodromal stages of disease will be necessary. ANN NEUROL 2024

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“…Our group and others have shown that RGS14 is integral for area CA2 pyramidal cell (PC) signaling and function (Montanez-Miranda et al, 2022). Based on recent reports of the protective capacity of RGS14 in peripheral tissue (Li et al, 2016; Zhang et al, 2022) and the newly appreciated contribution of area CA2 in TLE (Freiman et al, 2021; Haussler et al, 2016; Kilias et al, 2022; Whitebirch et al, 2022; Wittner et al, 2009), we hypothesized that RGS14 may serve a protective role in area CA2 following seizure insult.…”

Section: Discussionmentioning

confidence: 99%

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

Harbin

Lustberg

Hurst

et al. 2023

Preprint

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RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. There, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies show that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Utilizing proteomics, we saw loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found RGS14 KO dramatically increased 3-nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we observed worse neuronal injury in area CA3 (but none in CA2 or CA1), and a lack of microgliosis in CA1 and CA2 compared to WT. Together, our data demonstrates a newly appreciated neuroprotective role for RGS14 against intense seizure activity in hippocampus. Our findings are consistent with a model where, after seizure, RGS14 is upregulated to support mitochondrial function and prevent oxidative stress in CA2 PCs, limit seizure onset and hippocampal neuronal injury, and promote microglial activation in hippocampus.

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RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease

Cited by 7 publications

References 167 publications

Defining hippocampal area CA2 in the fox (Vulpes vulpes) brain

Defining hippocampal area CA2 in the fox (Vulpes vulpes) brain

Alterations in Blood Methylome as Potential Epigenetic Biomarker in Sporadic Parkinson's Disease

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

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