Deciphering the Differential Ubiquitination on Androgen Receptor Degradation in Kennedy’S Disease: from Mechanism to Therapy

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Kennedy's disease (KD), also known as X-linked spinal and bulbar muscular atrophy (SBMA), is an inherited disorder caused by CAG/polyglutamine (polyQ) repeat expansions in the human androgen receptor (AR) gene and is one of nine degenerative disorders that result from polyglutamine proteins. The pathological polyQ-expanded AR (polyQ-AR) protein undergoes hormone-dependent nuclear translocation, misfolding and aggregation, steps that are critical to the development of progressive proximal limb and bulbar muscle weakness in men that eventually lead to extreme disability. In terms of the disease management, there is no effective cure for this devastating disease. Previously, we uncovered endoplasmic reticulum (ER) stress as a defining cellular feature of misfolding AR aggregates by analyzing a stem cell and mouse models of KD/SBMA. However, the molecular pathways that degrade the polyQ-AR protein aggregation remain incompletely defined, and this lack of knowledge hinders the development of disease-modifying therapies. The objective of this grant application is to define the roles of the ubiquitin-proteasome machinery in the protein quality control decisions that govern polyQ-AR degradation. Our central hypothesis is that the specificity of ubiquitin modifications has essentially opposing roles in the triage of the polyQ-AR, in that Lysine 48-linked polyubiquitin chains promotes polyQ-AR proteins for degradation whereas Lysine 63-linked polyubiquitin chains prevents polyQ-AR proteins for destruction. This hypothesis springs from our preliminary data showing that misfolding of the polyQ-AR protein results in Lysine 63-linked polyubiquitin chains to block protein degradation. In contrast, activation of Lysine 48-mediated polyubiquitination promotes polyQ-AR protein degradation. The rationale of the proposed work is to elucidate the mechanisms that regulate polyQ-AR degradation and identify targets that can be exploited by the development of new therapies. Biochemical and pharmacological approaches will be combined with characterization of mouse behavioral and pathological changes to define the roles of differential polyubiquitinated polyQ-AR in a mouse model of KD/SBMA. We specifically aim to: AIM 1: To define different types of polyubiquitin chains in polyQ-AR which determine distinct protein function and cell fate. AIM 2: To investigate how activation of ubiquitin-proteasome degradation pathway promotes the protein clearance of the polyQ-AR inclusion bodies. AIM 3: To explore the therapeutically potential of targeting polyQ-AR degradation for reducing disease symptoms and histopathology in SBMA mice. These studies are expected to have a significant positive impact by defining the roles of polyubiquitinated polyQ-AR and thereby identifying potential therapeutic targets for KD/SBMA. As several degenerative disease-causing polyQ proteins are also targeted by the polyubiquitination, we anticipate that our findings will also serve as a paradigm for understanding the effects of different polyubiquitination on the phenotype of these related disorders.

Project IDs

Project ID:PC10901-0378
External Project ID:MOST107-2320-B182-035-MY3
StatusFinished
Effective start/end date01/08/2031/07/21

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