{"doi":"10.7302/4714","title":"A Mystery of Muscle: Establishing Mechanisms of Toxicity in Polyglutamine Disease","abstract":"Polyglutamine disorders encompass nine uniformly fatal diseases for which there are no disease course altering therapies. This group of related diseases share a key source: expansion of a CAG microsatellite repeat in genes which code for widely different proteins. Downstream of expansion, protein misfolding and oligomerization lead to gain-of-function proteotoxicity. Ultimately, this toxicity leads to disruption of a multitude of signaling pathways, altered homeostasis, and selective cell death. The first discovered polyglutamine disease is caused by an expansion of a CAG microsatellite repeat in the gene coding for androgen receptor and is called Kennedy’s Disease or Spinobulbar Muscular Atrophy (SBMA). Patients with this repeat expansion develop progressive degeneration of the neuromuscular system and are ultimately wheelchair bound. While the cause of SBMA is well-defined, the downstream consequences of receptor expansion remain poorly understood. Recently, several studies have implicated skeletal muscle as playing an important role in the pathogenesis of disease. However, despite two decades of study, the cause of muscle atrophy in SBMA remains poorly defined. This thesis will first outline polyglutamine diseases with a focus on SBMA. In Chapter 2, I discuss the data characterizing protein quality control in polyglutamine disease with a focus on the ubiquitin-proteasome system (UPS), which is both an important therapeutic target and critical mediator of muscle atrophy downstream of other sources. In Chapter 3, this thesis provides primary data demonstrating the surprising finding of age-dependent proteasome impairment, suggesting the proteasome does not account for muscle atrophy in SBMA. In Chapter 4, this thesis will delve examine potential sources of muscle atrophy in SBMA, implicating a key regulator of muscle hypertrophy as a novel therapeutic target in disease. In Chapter 5, the question of whether SBMA is accurately characterized as a neurodegenerative disease will be discussed, with primary data provided comparing changes in SBMA skeletal muscle to those caused by models of myopathy and neuropathy. Together, this data identifies a novel source of muscle atrophy downstream of polyglutamine proteins and defines several key questions for future studies.","journal":"Deep Blue (University of Michigan)","year":2020,"id":134909,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":590477,"name":"Samir Ranjan Nath","orcid":"0000-0002-4393-4781","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:27.963294Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}