The Role of Ubiquitination in Spinal and Bulbar Muscular Atrophy

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2022 Oct 24

PMID 36277484

Authors

Medha Sengupta

Anna Pluciennik

Diane E Merry

Affiliations

Soon will be listed here.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative and neuromuscular genetic disease caused by the expansion of a polyglutamine-encoding CAG tract in the androgen receptor (AR) gene. The AR is an important transcriptional regulator of the nuclear hormone receptor superfamily; its levels are regulated in many ways including by ubiquitin-dependent degradation. Ubiquitination is a post-translational modification (PTM) which plays a key role in both AR transcriptional activity and its degradation. Moreover, the ubiquitin-proteasome system (UPS) is a fundamental component of cellular functioning and has been implicated in diseases of protein misfolding and aggregation, including polyglutamine (polyQ) repeat expansion diseases such as Huntington's disease and SBMA. In this review, we discuss the details of the UPS system, its functions and regulation, and the role of AR ubiquitination and UPS components in SBMA. We also discuss aspects of the UPS that may be manipulated for therapeutic effect in SBMA.

Citing Articles

The Role of Mechanotransduction in Contact Inhibition of Locomotion and Proliferation.

Nakamura F Int J Mol Sci. 2024; 25(4).

PMID: 38396812 PMC: 10889191. DOI: 10.3390/ijms25042135.

A phenotypically robust model of spinal and bulbar muscular atrophy in Drosophila.

Richardson K, Sengupta M, Sujkowski A, Libohova K, Harris A, Wessells R J Neurosci Res. 2024; 102(1):e25278.

PMID: 38284836 PMC: 11237963. DOI: 10.1002/jnr.25278.

Regulation of androgen receptor stability by the β Pix/STUB1 complex.

Chahdi A, Jorgez C, Seth A FASEB J. 2024; 38(2):e23408.

PMID: 38197270 PMC: 11832013. DOI: 10.1096/fj.202301100R.

Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Blount J, Patel N, Libohova K, Harris A, Tsou W, Sujkowski A J Neurol Sci. 2023; 454:120828.

PMID: 37865002 PMC: 10841544. DOI: 10.1016/j.jns.2023.120828.

Huntingtin-associated protein 1-associated intracellular trafficking in neurodegenerative diseases.

Chen X, He E, Su C, Zeng Y, Xu J Front Aging Neurosci. 2023; 15:1100395.

PMID: 36824265 PMC: 9941194. DOI: 10.3389/fnagi.2023.1100395.

References

Rusilowicz-Jones E, Brazel A, Frigenti F, Urbe S, Clague M . Membrane compartmentalisation of the ubiquitin system. Semin Cell Dev Biol. 2021; 132:171-184. DOI: 10.1016/j.semcdb.2021.11.016. View

Bott L, Badders N, Chen K, Harmison G, Bautista E, Shih C . A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet. 2016; 25(10):1979-1989. PMC: 5062587. DOI: 10.1093/hmg/ddw073. View

Dejager S, Bry-Gauillard H, Bruckert E, Eymard B, Salachas F, Leguern E . A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab. 2002; 87(8):3893-901. DOI: 10.1210/jcem.87.8.8780. View

Park E, Dezhbord M, Lee A, Kim K . The Roles of Ubiquitination in Pathogenesis of Influenza Virus Infection. Int J Mol Sci. 2022; 23(9). PMC: 9105177. DOI: 10.3390/ijms23094593. View

Lieberman A, Shakkottai V, Albin R . Polyglutamine Repeats in Neurodegenerative Diseases. Annu Rev Pathol. 2018; 14:1-27. PMC: 6387631. DOI: 10.1146/annurev-pathmechdis-012418-012857. View

Northrop A, Vangala J, Feygin A, Radhakrishnan S . Disabling the Protease DDI2 Attenuates the Transcriptional Activity of NRF1 and Potentiates Proteasome Inhibitor Cytotoxicity. Int J Mol Sci. 2020; 21(1). PMC: 6982299. DOI: 10.3390/ijms21010327. View

Giridhar P, Williams K, VonHandorf A, Deford P, Kasper S . Constant Degradation of the Androgen Receptor by MDM2 Conserves Prostate Cancer Stem Cell Integrity. Cancer Res. 2019; 79(6):1124-1137. PMC: 6428062. DOI: 10.1158/0008-5472.CAN-18-1753. View

Sha Z, Goldberg A . Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr Biol. 2014; 24(14):1573-1583. PMC: 4108618. DOI: 10.1016/j.cub.2014.06.004. View

Nath S, Yu Z, Gipson T, Marsh G, Yoshidome E, Robins D . Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction. J Clin Invest. 2018; 128(8):3630-3641. PMC: 6063498. DOI: 10.1172/JCI99042. View

10.

Rinaldi C, Bott L, Chen K, Harmison G, Katsuno M, Sobue G . Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy. Mol Med. 2012; 18:1261-8. PMC: 3521783. DOI: 10.2119/molmed.2012.00271. View

11.

Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H . Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature. 2007; 446(7135):562-6. DOI: 10.1038/nature05683. View

12.

Grou C, Pinto M, Mendes A, Domingues P, Azevedo J . The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors. Sci Rep. 2015; 5:12836. PMC: 4522658. DOI: 10.1038/srep12836. View

13.

Berger T, Montie H, Jain P, Legleiter J, Merry D . Identification of novel polyglutamine-expanded aggregation species in spinal and bulbar muscular atrophy. Brain Res. 2015; 1628(Pt B):254-264. PMC: 4681586. DOI: 10.1016/j.brainres.2015.09.033. View

14.

Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y . Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain. 2005; 128(Pt 3):659-70. DOI: 10.1093/brain/awh381. View

15.

Wong C, Zhou Z, Sar M, Wilson E . Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains. J Biol Chem. 1993; 268(25):19004-12. View

16.

Chang L, Barford D . Insights into the anaphase-promoting complex: a molecular machine that regulates mitosis. Curr Opin Struct Biol. 2014; 29:1-9. DOI: 10.1016/j.sbi.2014.08.003. View

17.

Wiborg O, Pedersen M, Wind A, Berglund L, Marcker K, Vuust J . The human ubiquitin multigene family: some genes contain multiple directly repeated ubiquitin coding sequences. EMBO J. 1985; 4(3):755-9. PMC: 554252. DOI: 10.1002/j.1460-2075.1985.tb03693.x. View

18.

Lauwers E, Jacob C, Andre B . K63-linked ubiquitin chains as a specific signal for protein sorting into the multivesicular body pathway. J Cell Biol. 2009; 185(3):493-502. PMC: 2700384. DOI: 10.1083/jcb.200810114. View

19.

Elia A, Boardman A, Wang D, Huttlin E, Everley R, Dephoure N . Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response. Mol Cell. 2015; 59(5):867-81. PMC: 4560960. DOI: 10.1016/j.molcel.2015.05.006. View

20.

Guharoy M, Bhowmick P, Tompa P . Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System. J Biol Chem. 2016; 291(13):6723-31. PMC: 4807260. DOI: 10.1074/jbc.R115.692665. View