ArticleHuman molecular genetics2014
Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 77 citations in OpenAlex.
- Article
- Targeting androgen receptor stability and degradation: approaches for developing a therapy for spinal and bulbar muscular atrophy.Cell communication and signaling : CCS · 2025Review
- Research Progress on the Functional Regulation Mechanisms of ZKSCAN3.Biomolecules · 2025Review
- The Biological Roles of ZKSCAN3 (ZNF306) in the Hallmarks of Cancer: From Mechanisms to Therapeutics.International journal of molecular sciences · 2024Review
- The post-translational regulation of transcription factor EB (TFEB) in health and disease.EMBO reports · 2023Review
- Autophagy in Heart Failure: Insights into Mechanisms and Therapeutic Implications.Journal of cardiovascular development and disease · 2023Review
- Transcriptional regulation of autophagy and its implications in human disease.Cell death and differentiation · 2023Review
- The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases.CNS neuroscience & therapeutics · 2023Review
- N6-methyladenosine (m6A) RNA modification in the pathophysiology of heart failure: a narrative review.Cardiovascular diagnosis and therapy · 2022Review
- The role of autophagy-lysosomal pathway in motor neuron diseases.Biochemical Society transactions · 2022Review
- Endurance exercise ameliorates phenotypes ineLife · 2022Article
- The protective role of exercise against age-related neurodegeneration.Ageing research reviews · 2022Review
- Article
- Defective lysosome reformation during autophagy causes skeletal muscle disease.The Journal of clinical investigation · 2021Article
- Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment.Current opinion in neurology · 2020Review
- NFκB Regulates Muscle Development and Mitochondrial Function.The journals of gerontology. Series A, Biological sciences and medical sciences · 2020Article
- Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases.Cellular and molecular life sciences : CMLS · 2020Review
- Article
- A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases.Frontiers in aging neuroscience · 2020Article
- Multifaceted role of SMCR8 as autophagy regulator.Small GTPases · 2020Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
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Abstract
Spinobulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in exon 1 of the androgen receptor (AR) gene. SBMA demonstrates androgen-dependent toxicity due to unfolding and aggregation of the mutant protein. There are currently no disease-modifying therapies, but of increasing interest for therapeutic targeting is autophagy, a highly conserved cellular process mediating protein quality control. We have previously shown that genetic manipulations inhibiting autophagy diminish skeletal muscle atrophy and extend the lifespan of AR113Q knock-in mice. In contrast, manipulations inducing autophagy worsen muscle atrophy, suggesting that chronic, aberrant upregulation of autophagy contributes to pathogenesis. Since the degree to which autophagy is altered in SBMA and the mechanisms responsible for such alterations are incompletely defined, we sought to delineate autophagic status in SBMA using both cellular and mouse models. Here, we confirm that autophagy is induced in cellular and knock-in mouse models of SBMA and show that the transcription factors transcription factor EB (TFEB) and ZKSCAN3 operate in opposing roles to underlie these changes. We demonstrate upregulation of TFEB target genes in skeletal muscle from AR113Q male mice and SBMA patients. Furthermore, we observe a greater response in AR113Q mice to physiological stimulation of autophagy by both nutrient starvation and exercise. Taken together, our results indicate that transcriptional signaling contributes to autophagic dysregulation and provides a mechanistic framework for the pathologic increase of autophagic responsiveness in SBMA.
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