Suppressor of cytokine signaling 2 is induced in Huntington’s Disease and involved in autophagy
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ABSTRACT:
PROVIDER: PRJNA1157311 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30548876.fastq.gz | Fastqsanger.gz | |||
| SRR30548877.fastq.gz | Fastqsanger.gz | |||
| SRR30548878.fastq.gz | Fastqsanger.gz | |||
| SRR30548879.fastq.gz | Fastqsanger.gz | |||
| SRR30548880.fastq.gz | Fastqsanger.gz |
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Project description:Suppressor of cytokine signaling (SOCS) proteins are primarily feedback inhibitors of cytokine signaling. The two conserved domains of SOCS proteins have distinct functions. Src homology 2 (SH2) domain inhibits cytokine receptor, while SOCS box acts as an E3 ubiquitin ligase. SOCS2, a cytokine signaling suppressor, has been primarily implicated in regulating inflammatory conditions in neuronal diseases. However, SOCS proteins have been suggested to play diverse roles in healthy and diseased nervous system including neurodegenerative disorders. In this study, SOCS2 was found to be upregulated in Huntington’s disease and was substantially induced in extended polyglutamine (polyQ)-expressing striatal cells. The induced level was augmented under aging conditions. In extended polyQ-expressing cells, downregulated SOCS2 improved autophagic dysfunction rather than altered inflammatory conditions. Overall, we suggest that SOCS2 involves in regulating autophagy by functioning as an E3 ligase in extended polyQ conditions, and consequently regulates cell damage and cell death type.
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Project description:Xu J, Kong L, Oliver B, Li B, Creasey EA, Guzman G, Schenone M, Carey KL, Carr SA, Graham DB, Deguine J, Xavier RJ. 2023. Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine autophagy in the context of inflammatory conditions are lacking. Here, using mouse models with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production in models of inflammation and adherent-invasive Escherichia coli (AIEC) infection. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify novel mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.
2023-06-06 | MSV000092110 | MassIVE
Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD in the lab has proven challenging as rodent models poorly reproduce the disease process and cellular models fail to include age-dependent processes crucial to the disease. Here we generated induced neurons (iNs) that retained age-dependent epigenetic characteristics of the donors through direct reprogramming of skin fibroblasts. HD-iNs displayed a transcriptionally regulated, distinct neurite specific alteration in autophagy, characterized by reduced transport of late autophagic structures and subsequent cargo degradation. In addition, HD-iNs displayed shorter, smaller and fewer neurites. CRISPRi-mediated silencing of both HTT alleles did not rescue the morphology nor the autophagic defect in HD-iNs. Strikingly, it resulted in additional autophagy alterations when done using ctrl-iNs, highlighting the importance of wt HTT in neuronal autophagy. In summary, our results have identified a distinct subcellular autophagy impairment in aged patient derived HD-neurons. In addition, we have shown a role for normal wt HTT in autophagy. Together this work provides a new rational for future development of autophagy activation therapies while also highlighting problems that may arise using non allele specific HTT silencing approaches, some of which are now in clinical trials.
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Project description:Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine autophagy in the context of inflammatory conditions are lacking. Here, using mouse models with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production in models of inflammation and adherent-invasive Escherichia coli (AIEC) infection. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify novel mechanistic targets downstream of autophagy. Our study reveals glutamine metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.
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Project description:Direct neuronal conversion of fibroblasts from Huntington’s disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD.
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Project description:Huntington’s disease (HD) is an inherited neurodegenerative disorder that is caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD in the lab has proven challenging as rodent models poorly reproduce the disease process and cellular models fail to include age-dependent processes crucial to the expression of the disease clinically. Here we generated induced neurons (iNs) through direct reprogramming of skin fibroblasts from HD-patients. This resulted in the generation of patient-derived HD neurons that retained age-dependent epigentic characteristics of the donors. Using these cells, we then undertook a proteomic analysis and demonstrated there was an alteration in the CAMKK-AMPK pathway and autophagy in these HD-iNs, compared to healthy control iN cells. In line with this, HD-iNs displayed a distinct subcellular alteration in autophagy, specifically in the neurites, characterized by a reduction in the transport of late autophagic structures between neurites and the soma and subsequent cargo degradation. In addition to which the HD-iNs displayed shorter, smaller and fewer neurites. CRISPRi-mediated silencing of HTT (both wt and mutant) did not rescue the morphology nor could this rescue the autophagic defect in HD-iNs and indeed resulted in additional autophagy alterations when done using ctrl-iNs, highlighting the importance of wild type HTT in neuronal autophagy. In summary, our results have identified a distinct subcellular autophagy impairment in aged patient derived HD-neurons. In addition, we have shown a role for normal wt Htt in autophagy. Together this work provides a new rational for future development of autophagy activation therapies while also highlighting problems that may arise using non allele specific htt silencing approaches, some of which are now in clinical trials.
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Project description:Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration. We developed hepatocyte-specific Socs3 knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after 2/3 partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after 2/3 PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic kinases extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor (EGF) or interleukin 6 (IL-6) stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes after PH, which fall into diverse physiologic categories. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma (HCC) at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiologic and neoplastic proliferative processes in the liver, and may act as a tumor suppressor. Keywords: SOCS3, liver regeneration
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Project description:Genome-wide association studies have identified Genetic Modifiers of HD (GeM-HD) comprised of polymorphic gene variants associated with accelerated or delayed onset of Huntington’s disease (HD). However, GeM-HD genes that contribute to neurodegeneration in HD remain underexplored. Here, we used medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of symptomatic HD patients (HD-MSNs), which recapitulate adult-onset neurodegenerative pathology of HD, to uncover genes whose reduced function alleviated HD-associated neurodegeneration. We identified RCAN1 whose knockdown (KD) robustly mitigated mutant HTT toxicity. RCAN1 KD enhanced chromatin accessibility of genes involved in longevity and autophagy through promoting Calcineurin and TFEB function. We reveal that G2 compounds, analogs of glibenclamide with autophagy enhancer activities, can mimic the RCAN1 KD-mediated neuroprotection by reducing the RCAN1-Calcineurin interaction, thereby promoting dephosphorylation and nuclear localization of TFEB. Our results indicate RCAN1 as a potential therapeutic target whose perturbation can increase neuronal resilience against neurodegeneration in HD.
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