Mutations in CHMP2B Causes Impaired Autophagy and Distorted Energy Metabolism cumulating in Reactive Astrocyte Phenotypes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE141388 | GEO | 2021/10/04
REPOSITORIES: GEO
Similar Datasets
Project description:Mutations in CHMP2B Causes Impaired Autophagy and Distorted Energy Metabolism cumulating in Reactive Astrocyte Phenotypes
| PRJNA593246 | ENA
Project description:Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.
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Project description:Although genetic testing is increasingly used in clinical nephrology, a large number of patients with congenital abnormalities of the kidney and urinary tract (CAKUT) remain undiagnosed with current gene panels. Therefore, careful curation of novel genetic findings is key to improving diagnostic yields. We recently described a novel intellectual disability syndrome caused by de novo heterozygous loss-of-function mutations in the gene encoding the splicing factor SON. Here, we show that many of these patients, including two previously unreported, exhibit a wide array of kidney abnormalities. Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts. Recurrent urinary tract infections, electrolyte disturbances, and hypertension were also observed in some patients. SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency. Taken together, our data suggest that the wide spectrum of phenotypes in patients with a pathogenic SON mutation is a consequence of impaired pre-mRNA splicing of several CAKUT genes. We propose that genetic testing panels designed to diagnose children with a kidney phenotype should include the SON gene.
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Project description:Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration--defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.
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Project description:Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.
| S-EPMC5260994 | biostudies-literature
Project description:To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4+ T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4+ T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4+ T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.
2019-11-12 | GSE131407 | GEO
Project description:The degradation of nonfunctional mitochondrial proteins is of fundamental relevance for maintenance of cellular homeostasis. The heteromeric CLPXP protein complex in the mitochondrial matrix is part of this process. In the fungal aging model Podospora anserina, ablation of CLPXP leads to an increase in healthy lifespan. Here, we report that this counterintuitive increase depends on a functional autophagy machinery. In PaClpXP mutants, autophagy is involved in energy conservation and the compensation of impairments in respiration. Strikingly, despite the impact on mitochondrial function, it is not mitophagy but general autophagy that is constitutively induced and required for longevity. In contrast, in another long-lived mutant ablated for the mitochondrial PaIAP protease, autophagy is neither induced nor required for lifespan extension. Our data provide novel mechanistic insights into the capacity of different forms of autophagy to compensate impairments of specific components of the complex mitochondrial quality control network and about the biological role of mitochondrial CLPXP in the control of cellular energy metabolism.
| S-EPMC5506401 | biostudies-literature
Project description:Astrocytes contribute to the pathogenesis of multiple sclerosis (MS); however, the mechanisms underlying the regulation of astrocytic responses remain unknown. Here we report an exhaustive molecular and functional characterization of astrocyte reactivity following exposure to cerebrospinal fluid (CSF) from MS patients classified according to the degree of inflammatory activity. We showed that mouse astrocytes exposed to CSF from patients with high inflammatory activity (MS-High) exhibited a specific pro-inflammatory reactive state that was characterized by enhanced NF-kB signalling. This reactive astrocyte state conferred a dysfunctional response through an altered pro-inflammatory secretome that drove neuronal dysfunction and impaired synaptic plasticity. SerpinE1 was identified as a potential downstream mediator of the non-cell-autonomous toxic effect on neuronal function based on its significant up-regulation in secretomes from astrocytes exposed to CSF from MS-high patients. Further, we identified chitinase 3-like 1 as a potential upstream modulator of astrocyte reactivity via activation of NF-kB signalling based on its significantly increased levels in the CSF from MS-High patients. Taken together our findings indicate that the inflammatory microenvironment in the central nervous system of MS patients can induce specific reactive astrocyte states that trigger neuronal degeneration and may ultimately contribute to disease progression.
2022-06-23 | PXD027152 | Pride
Project description:Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells.
| S-EPMC8282463 | biostudies-literature
Project description:IntroductionObesity has becoming a global health issue. Fetus exposed to adversity in the uterine are susceptible to unhealth stimulus in adulthood. Prenatal inflammation is related to poor neonatal outcomes like neurodevelopmental impairments and respiratory complications. Recent studies suggested prenatal lipopolysaccharide (LPS) exposure could result in metabolic disorders. Thus, we hypothesized that offspring exposed to prenatal inflammation could develop into metabolic disorder.MethodsThe pregnant C57BL/6J mice were intraperitoneally injected with 50 μg/kg LPS or saline only once at GD15. The male offspring were weighted weekly until sacrificed. Indirect calorimetry and body composition were both performed at 9 and 18 weeks old. At 20 weeks old, mice were fasted overnight before collecting blood samples and liver for metabolomics analysis and RNA sequencing, respectively. Differentially expressed genes were further verified by RT-qPCR and western blotting.ResultsPrenatal inflammation resulted in obesity with increased fat percentage and decreased energy expenditure in middle-age male offspring. Abnormal lipid accumulation, changes of gene expression profile and upregulation of multi-component mechanistic target of rapamycin complex 1 (mTOR)/Peroxisome proliferator-activated receptor-γ pathway was observed in liver, accompanied with decreased bile acids level, unsaturated fatty acids androgens and prostaglandins in serum. Indirect calorimetry showed increased respiratory exchange rate and deceased spontaneous activity at 9 weeks in LPS group. Impaired energy expenditure was also observed at 18 weeks in LPS group.ConclusionPrenatal LPS exposure led to obesity and abnormal lipid metabolism through impaired energy expenditure.
| S-EPMC8822840 | biostudies-literature