Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone

He, Wen-Tian; Zheng, Xueming; Zhang, Yuhang; Gao, Yong-Guang; Song, Ai-Xin; Goot, F. Gisou van der; Hu, Hongyu

doi:10.1371/journal.pone.0147515

Cited by 35 publications

(45 citation statements)

References 41 publications

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“…Whereas Hsp90β was increased in the brainstem [20], both Hsp90α and Hsp90β were decreased in the cervical spinal cord of Q84 mice. Others and us have previously shown that decreased abundance of Hsp90, or its inhibition by 17-DMAG, correlates directly with reduction of mutant ATXN3 levels and improvement of pathological and motor phenotypes in animal models of MJD [20,35,46,47]. Indeed, in this pre-clinical trial of citalopram in Q84 mice, we confirmed the existence of a direct correlation of HMW species of ATXN3 to Hsp90β abundance in the brainstem and spinal cord ( Supplementary Fig.…”

Section: Discussionsupporting

confidence: 84%

Citalopram Reduces Aggregation of ATXN3 in a YAC Transgenic Mouse Model of Machado-Joseph Disease

et al. 2018

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Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is a fatal polyglutamine disease with no disease-modifying treatment. The selective serotonin reuptake inhibitor citalopram was shown in nematode and mouse models to be a compelling repurposing candidate for Machado-Joseph disease therapeutics. We sought to confirm the efficacy of citalopram to decrease ATXN3 aggregation in an unrelated mouse model of Machado-Joseph disease. Four-week-old YACMJD84.2 mice and non-transgenic littermates were given citalopram 8 mg/kg in drinking water or water for 10 weeks. At the end of treatment, brains were collected for biochemical and pathological analyses. Brains of citalopram-treated YACMJD84.2 mice showed an approximate 50% decrease in the percentage of cells containing ATXN3-positive inclusions in the substantia nigra and three examined brainstem nuclei compared to controls. No differences in ATXN3 inclusion load were observed in deep cerebellar nuclei of mice. Citalopram effect on ATXN3 aggregate burden was corroborated by immunoblotting analysis. While lysates from the brainstem and cervical spinal cord of citalopram-treated mice showed a decrease in all soluble forms of ATXN3 and a trend toward reduction of insoluble ATXN3, no differences in ATXN3 levels were found between cerebella of citalopram-treated and vehicle-treated mice. Citalopram treatment altered levels of select components of the cellular protein homeostatic machinery that may be expected to enhance the capacity to refold and/or degrade mutant ATXN3. The results here obtained in a second independent mouse model of Machado-Joseph disease further support citalopram as a potential drug to be repurposed for this fatal disorder.

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Section: Discussionsupporting

confidence: 84%

Citalopram Reduces Aggregation of ATXN3 in a YAC Transgenic Mouse Model of Machado-Joseph Disease

et al. 2018

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“…As a client protein of HSP90, Htt is regulated by the HSP90 chaperone system in cell. We have previously reported that the cytoplasmic isoform of a deubiquitinating enzyme USP19 (USP19_b) cooperates with HSP90 and regulates the protein level and aggregation of Htt 31 . However, whether the regulatory function of USP19_b relies on the interaction between HSP90 and Htt is not clear.…”

Section: Resultsmentioning

confidence: 99%

“…USP19_b could promote the aggregation of polyQ-expanded Htt 31 . To verify the effect of HSP90-Htt-N interaction, we performed a filter trap experiment to detect the aggregates formed by polyQ-expanded Htt-N90.…”

Section: Resultsmentioning

confidence: 99%

“…Also, how HSP90 participates in the stabilization and degradation of Htt needs to be clearly elucidated. Our previous study has demonstrated that cytoplasmic ubiquitin-specific protease 19 (USP19), through interacting with HSP90, up-regulates the protein levels of the N-terminal 552-residue fragments of Htt (Htt-N552) with normal and expanded polyQ, and consequently increases the aggregates formed by polyQ-expanded Htt-N552 31 . Here, we investigated the interactions between HSP90 and the N-terminal fragments of Htt by biochemical and biophysical approaches.…”

Section: Introductionmentioning

confidence: 99%

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HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19

He¹,

Xue²,

Gao³

et al. 2017

Sci Rep

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Huntington’s disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract. Structural integration of the middle and C-terminal domains of HSP90 is essential for interacting with Htt-N90, and the dimerization mediated by the C-terminal domain facilitates this interaction. Moreover, ubiquitin-specific protease 19 (USP19), a deubiquitinating enzyme interacting with HSP90, up-regulates the protein level of Htt-N90 and consequently promotes its aggregation, whereas disruption of the interaction between Htt-N90 and HSP90 attenuates the effect of USP19 on Htt-N90. Thus, HSP90 interacts with Htt-N90 on the N-terminal amphipathic α-helix, and then recruits USP19 to modulate the protein level and aggregation of Htt-N90. This study provides mechanistic insights into the recognition between HSP90 and the N-terminus of Htt, and the triage decision for the Htt protein by the HSP90 chaperone system.

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“…Interestingly, the proteins upregulated suggested a role in stabilizing, rather than degrading Httex1. This included deubiquitinating enzyme Usp19, which has been previously reported to stabilize mutant Httex1 levels and promote its aggregation into less toxic aggregates by Hsp90 (102,103). Rock2 was also increased, which has previously been suggested to slow degradation of Httex1 (104).…”

Section: Supplementary Note 1 Expanded Discussion Of Proteins That Cmentioning

confidence: 96%

Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

Sui

Pires

Nie

et al. 2019

Preprint

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The accumulation of protein deposits in neurodegenerative diseases involves the presence of a metastable subproteome vulnerable to aggregation. To investigate this subproteome and the mechanisms that regulates it, we measured the proteome solubility of the Neuro2a cell line under protein homeostasis stresses induced by Huntington Disease proteotoxicity; Hsp70, Hsp90, proteasome and ERmediated folding inhibition; and oxidative stress. We found one-quarter of the proteome extensively changed solubility. Remarkably, almost all the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodelling of protein complexes involved in adaptation to perturbation, most notably stress granule proteins, which responded differently to different stresses. These results indicate that the robustness of protein homeostasis relies on the absence of proteins highly vulnerable to aggregation and on large changes in aggregation state of regulatory mechanisms that restore protein solubility upon specific perturbations.2

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Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone

Cited by 35 publications

References 41 publications

Citalopram Reduces Aggregation of ATXN3 in a YAC Transgenic Mouse Model of Machado-Joseph Disease

Citalopram Reduces Aggregation of ATXN3 in a YAC Transgenic Mouse Model of Machado-Joseph Disease

HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19

Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

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