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Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy
Anna Pluciennik, … , Sokol V. Todi, Diane E. Merry
Anna Pluciennik, … , Sokol V. Todi, Diane E. Merry
Published November 10, 2020
Citation Information: J Clin Invest. 2021;131(1):e134565. https://doi.org/10.1172/JCI134565.
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Research Article Neuroscience Article has an altmetric score of 5

Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy

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Abstract

Polyglutamine (polyQ) diseases are devastating, slowly progressing neurodegenerative conditions caused by expansion of polyQ-encoding CAG repeats within the coding regions of distinct, unrelated genes. In spinal and bulbar muscular atrophy (SBMA), polyQ expansion within the androgen receptor (AR) causes progressive neuromuscular toxicity, the molecular basis of which is unclear. Using quantitative proteomics, we identified changes in the AR interactome caused by polyQ expansion. We found that the deubiquitinase USP7 preferentially interacts with polyQ-expanded AR and that lowering USP7 levels reduced mutant AR aggregation and cytotoxicity in cell models of SBMA. Moreover, USP7 knockdown suppressed disease phenotypes in SBMA and spinocerebellar ataxia type 3 (SCA3) fly models, and monoallelic knockout of Usp7 ameliorated several motor deficiencies in transgenic SBMA mice. USP7 overexpression resulted in reduced AR ubiquitination, indicating the direct action of USP7 on AR. Using quantitative proteomics, we identified the ubiquitinated lysine residues on mutant AR that are regulated by USP7. Finally, we found that USP7 also differentially interacts with mutant Huntingtin (HTT) protein in striatum and frontal cortex of a knockin mouse model of Huntington’s disease. Taken together, our findings reveal a critical role for USP7 in the pathophysiology of SBMA and suggest a similar role in SCA3 and Huntington’s disease.

Authors

Anna Pluciennik, Yuhong Liu, Elana Molotsky, Gregory B. Marsh, Bedri Ranxhi, Frederick J. Arnold, Sophie St.-Cyr, Beverly Davidson, Naemeh Pourshafie, Andrew P. Lieberman, Wei Gu, Sokol V. Todi, Diane E. Merry

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Figure 2

USP7 preferentially interacts with AR112Q in cells.

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USP7 preferentially interacts with AR112Q in cells.
(A) Co-IP of USP7 wi...
(A) Co-IP of USP7 with AR after pull-down with an anti-AR antibody, followed by immunoblot with anti-AR or anti-USP7 antibodies; GAPDH detection served as loading control. Input levels of AR or USP7 in AR112Q- relative to AR10Q-expressing cells are shown in blue (data normalized to AR10Q cells). Relative amounts of immunoprecipitated AR or USP7 are shown in red, normalized to IP recovery from AR10Q-expressing cells. (B) Co-IP of AR with USP7 following pull-down with an anti-USP7 antibody, followed by immunoblot with anti-AR or anti-USP7 antibodies; GAPDH detection served as loading control. As in A, relative input levels are shown in blue, and amounts of immunoprecipitated proteins are shown in red. (C) USP7-AR interaction was evaluated by PLA (red puncta) in PC12 cells. AR was predominantly nuclear, as judged by subsequent immunostaining with anti-AR antibody (green signal). Scale bar: 10 μm. (D) Quantification of PLA puncta in cells expressing AR10Q and AR112Q, respectively, based on images taken before staining for total AR (see Supplemental Figure 2C), with 100 cells evaluated per condition and carried out in triplicate. P < 0.0001, Kolmogorov-Smirnov test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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