Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease

Chhetri, Gaurav; Ke, Yuting; Wang, Ping; Usman, Muhammad; Li, Yan; Sapp, Ellen; Wang, Jing; Ghosh, Arabinda; Islam, Md. Ariful; Wang, Xiaolong; Boudi, Adel; DiFiglia, Marian; Li, Xueyi

doi:10.1083/jcb.202112073

Cited by 7 publications

(6 citation statements)

References 73 publications

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“…For example, Huntington's disease model mice exhibit decreased cell surface expression of channel proteins, which are essential for presynaptic neurotransmitter release [ 68 ]. Chhetri et al [ 19 ] recently reported that the expression of mutant huntingtin with long polyQ tracts (HTT Q111) interfered with the endosomal vesicular trafficking and cell surface expression of membrane-bound receptors and transporters [ 19 , 69 ]. These reports imply that alterations in vesicular trafficking in neurodegenerative disorders are caused by polyglutamine expansion.…”

Section: Discussionmentioning

confidence: 99%

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex

Hagiwara,

Minami,

Ushio

et al. 2023

Biochemical Journal

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Inclusion body formation is associated with cytotoxicity in a number of neurodegenerative diseases. However, the molecular basis of the toxicity caused by the accumulation of aggregation-prone proteins remains controversial. In this study, we found that disease-associated inclusions induced by elongated polyglutamine chains disrupt the complex formation of BAG6 with UBL4A, a mammalian homologue of yeast Get5. UBL4A also dissociated from BAG6 in response to proteotoxic stresses such as proteasomal inhibition and mitochondrial depolarization. These findings imply that the cytotoxicity of pathological protein aggregates might be attributed in part to disruption of the BAG6-UBL4A complex that is required for the biogenesis of tail-anchored proteins.

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Section: Discussionmentioning

confidence: 99%

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex

Hagiwara,

Minami,

Ushio

et al. 2023

Biochemical Journal

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“…We first investigated the expression and mutation profiles of 159 necroptosis-related genes in ccRCC patients in TCGA and found that 18 necroptosis-related genes play an important role in ccRCC. Some studies have shown that gene mutations play a guiding role in the occurrence of diseases such as cancer and the prognosis of cancer patients ( 42 – 45 ). Therefore, we explored the variation of 18 key necroptosis-related genes.…”

Section: Discussionmentioning

confidence: 99%

A novel necroptosis-related long noncoding RNA model for predicting clinical features, immune characteristics, and therapeutic response in clear cell renal cell carcinoma

Zhang

Chen

et al. 2023

Front. Immunol.

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BackgroundNecroptosis is an immune-related cell death pathway involved in the regulation of the tumor microenvironment (TME). Here, we aimed to explore the role of necroptosis in clear cell renal cell carcinoma (ccRCC) and construct a necroptosis-related lncRNA (NRL) model to assess its potential association with clinical characteristics and immune status.MethodsGene expression profiles and clinical data for ccRCC patients were obtained from the Cancer Genome Atlas (TCGA). Pearson’s correlation, univariate Cox, and least absolute shrinkage and selection operator analyses were used to develop an NRL model. Kaplan–Meier (K-M) and receiver operating characteristic (ROC) curve analyses were used to determine the prognostic value of the NRL model. The clinical information was used to assess the diagnostic value of the NRL model. The TME, immune function, immune cell infiltration, and immune checkpoints associated with the NRL model risk score were studied using the ESTIMATE, GSEA, ssGSEA, and CIBERSORT algorithms. The immunophenoscore (IPS) and half-maximal inhibitory concentration (IC50) were used to compare the efficacies of immunotherapy and chemotherapy based on the NRL model. Finally, in vitro assays were performed to confirm the biological roles of NRLs.ResultsA total of 18 necroptosis-related genes and 285 NRLs in ccRCC were identified. A four-NRL model was constructed and showed good performance in the diagnosis and prognosis of ccRCC patients. The ESTIMATE scores, tumor mutation burden, and tumor stemness indices were significantly correlated with NRL model risk score. Immune functions such as chemokine receptors and immune receptor activity showed differences between different risk groups. The infiltration of immunosuppressive cells such as Tregs was higher in high-risk patients than in low-risk patients. High-risk patients were more sensitive to immunotherapy and some chemotherapy drugs, such as sunitinib and temsirolimus. Finally, the expression of NRLs included in the model was verified, and knocking down these NRLs in tumor cells affected cell proliferation, migration, and invasion.ConclusionNecroptosis plays an important role in the progression of ccRCC. The NRL model we constructed can be used to predict the clinical characteristics and immune features of ccRCC patients.

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“…Immunolabeling was performed with floating brain sections with procedures as previously described ( 40, 95 ). Sections were removed from cryoprotectant solution and washed three times in PBS at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9

Li,

Usman,

Sapp

et al. 2024

Preprint

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Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). Trappc9-deficient mice gain body weight normally in early developmental periods but become overweight shortly after being weaned. Here, we report that trappc9 deficiency in mice disrupts systemic glucose homeostasis and triggers the onset of obesity and NAFLD. Chronic treatment combining drugs suppressing dopamine receptor D1 (DRD1) and stimulating DRD2 restores systemic glucose homeostasis and counteracts abnormal body weight gain and lipid accumulation in adipose and liver tissues in trappc9-deficient mice. Additional pharmacological studies imply that the disruption of systemic glucose homeostasis in trappc9-deficient mice originates from deficient stimulation of DRD2 in the brain. Transcriptomic and proteomic analyses reveal signs of impairments in dopamine secretion in trappc9-deficient mice. Brain examinations indicate that trappc9-deficient mice synthesize dopamine normally, but their dopamine-secreting neurons have a lower abundance of structures for releasing dopamine. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine neurotransmission.

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Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease

Cited by 7 publications

References 73 publications

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex

A novel necroptosis-related long noncoding RNA model for predicting clinical features, immune characteristics, and therapeutic response in clear cell renal cell carcinoma

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9

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