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DJ1 ablation enhances CMA activity to exacerbate BAT whitening in humanized mice

ABSTRACT: Humans predominantly live under thermoneutral conditions, leading to brown adipose tissue (BAT) whitening, a reduction in mitochondrial content and thermogenesis. Here, the adaptations to thermal stress of BAT are examined using quantitative proteomics, finding that Parkinson’s disease (PD) pathways are sensitive to ambient temperature. Ablation of DJ-1, a PD gene, exaggerates BAT whitening, resulting in impaired insulin sensitivity and energy expenditure at thermoneutrality. We further identify that the activity of chaperon-mediated autophagy (CMA) contributes to the deletion of DJ-1-induced metabolic phenotypes. Importantly, DJ-1 interacts with HSC70 and subsequently decreases the activity of CMA, enhances the stability of thermogenic proteins. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A counteracts the phenotypes induced by DJ-1 ablation. Additionally, while 4-PBA, an agonist of DJ-1, upregulates mitochondrial oxygen consumption; compound 23, an antagonist of DJ-1, exerts the opposite effects. Collectively, these data address a cell-autonomous route to regulate BAT whitening at thermoneutrality.

ORGANISM(S): Mus musculus

PROVIDER: GSE239793 | GEO | 2025/03/07

REPOSITORIES: GEO

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Project description:Despite extensive investigation of Parkinson's disease (PD), rending oxidative stress, mitochondrial dysfunction, altered proteostasis, and abnormal insulin signaling as potential mechanisms, however, etiology of most cases remains undefined. To reveal the underlying mechanism and determine the correlation of SH2B1 expression and Parkinson’s disease, we monitored the related gene levels during PD progress in humans and mice. For human subjects, we collected plasma from Parkinson’s patients (PD, diagnosed by clinicians and non-PD controls (NC, because brain samples are not available) and performed whole-transcriptome gene expression analysis. The transcriptome microarray enabled detection of the differential expression of 3229 transcripts (FPKM >= 0.1; cutoff of 2.0-fold change; p < 0.05) and further filtering of 952 transcripts (588 up-, 364 down-regulated transcripts in PD; reads > 5, p < 0.05).Based on the unbiased analysis, we revealed that SH2B1, but not SH2B2 or SH2B3, was reduced in PD patients’ plasma. Real-time quantitative polymerase chain reaction (qPCR) confirmed that there was decreased expression of SH2B1 in PD patients’ plasma as well as in plasma from MPTP/p induced murine PD model. SH2B1 is an intracellular adaptor protein that assists signal transduction of several receptor-tyrosine-kinases and elicits beneficial metabolic effects in obesity. Here, we show that SH2B1 is a key component of molecular chaperone autophagy (CMA) that preserves dopaminergic neuron health and counters MPTP/p-induced PD in mice. Sh2b1 deficiency accelerated neuron apoptosis in PD mouse. In contrast, transgenic expression of Sh2b1 in neurons alleviated MPTP/p-induced injury. SH2B1 attenuated neuron apoptosis by binding HSC70 to promote CMA degradation of PLIN4, a lipid droplets (LDs) surrounding protein, thus suppressed PLIN4/LDs mediated lipid peroxidation stress in PD mice brain. Adeno-associated virus–mediated (AAV-mediated) rescue of neuron HSC70 expression in wildtype not Sh2b1-deficent mice functionally restored the neuropathology of PD. Thus, neuronal SH2B1 serves as an assistant in CMA rather than insulin signaling by promoting a CMA substrate degradation to counter MPTP/p-induced neurodegeneration.

Project description:Background and aim: The molecular mechanisms underlying the progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) remain unclear; however, the role of autophagy in these mechanisms has attracted extensive attention. This study aimed to investigate the role of chaperone-mediated autophagy (CMA) in NAFL-to-NASH progression and elucidate the underlying mechanisms. Methods: Hepatic CMA activity was analyzed in patients with NASH and mouse models of NASH. LAMP2A was knocked down or overexpressed to assess the effects of hepatocyte-specific CMA on NAFL-to-NASH progression. Mice were fed a high-fat diet or a methionine–choline-deficient diet to induce NAFL or NASH. Palmitic acid was used to mimic lipotoxicity-induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via chromatin immunoprecipitation and dual-luciferase reporter assay. Results: Hepatic CMA activity was substantially low in patients and mice with NASH. Knockdown of LAMP2A resulted in hepatocyte-specific CMA deficiency, which promoted hepatic inflammation and fibrosis in mice with NASH. In addition, CMA deficiency exacerbated endoplasmic reticulum (ER) stress and hepatocyte damage in vivo and in vitro. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of HMGCR, a rate-limiting enzyme of cholesterol synthesis, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. Restoration of hepatocyte-specific CMA activity effectively ameliorated diet-induced NASH and ER stress in vivo and in vitro. FOXM1 negatively regulated the transcription of LAMP2A by directly binding to its promoter. Upregulation of FOXM1 impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious circle and promoting the development of NASH. Conclusions: This study highlights the role of the FOXM1/CMA/ER stress axis in NAFL-to-NASH progression and proposes novel therapeutic targets for NASH.

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DJ1 ablation enhances CMA activity to exacerbate BAT whitening in humanized mice

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