title: Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy.
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.
authors.affiliation: Departments of Pathology and.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Chua
authors.forename: Satya L
authors.initials: SL
authors.lastname: Reddy
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Diane M
authors.initials: DM
authors.lastname: Robins
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D010805:Physical Conditioning, Animal; D011944:Receptors, Androgen / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D010455:Peptides; D011944:Receptors, Androgen; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; C535120:ZKSCAN3 protein, mouse; C097188:polyglutamine