title: A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA, Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden, laura.bott@northwestern.edu.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bott
authors.affiliation: Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Nisha M
authors.initials: NM
authors.lastname: Badders
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: Ke-Lian
authors.initials: KL
authors.lastname: Chen
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Harmison
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Bautista
authors.affiliation: AndroScience Corporation, Solana Beach, CA 92075, USA and.
authors.forename: Charles C-Y
authors.initials: CC
authors.lastname: Shih
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
mesh_terms: D000818:Animals; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D055785:Gene Knockdown Techniques; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051265:NF-E2-Related Factor 1 / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000235:genetics; D017510:Protein Folding / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage; D014157:Transcription Factors / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C410798:AR protein, human; C000621364:ASC-JM17; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D000076249:Heat Shock Transcription Factors; C053134:Hsf protein, Drosophila; D051265:NF-E2-Related Factor 1; D051267:NF-E2-Related Factor 2; D010455:Peptides; D011944:Receptors, Androgen; D054852:Small Molecule Libraries; D014157:Transcription Factors; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin