A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy

• Published in: Human molecular genetics Vol. 25; no. 10; pp. 1979 - 1989
• Main Authors: Bott, Laura C, Badders, Nisha M, Chen, Ke-Lian, Harmison, George G, Bautista, Elaine, Shih, Charles C-Y, Katsuno, Masahisa, Sobue, Gen, Taylor, J Paul, Dantuma, Nico P, Fischbeck, Kenneth H, Rinaldi, Carlo
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.05.2016
• Subjects: Animals; Bulbo-Spinal Atrophy, X-Linked - drug therapy; Bulbo-Spinal Atrophy, X-Linked - genetics; Bulbo-Spinal Atrophy, X-Linked - pathology; Curcumin - administration & dosage; Curcumin - analogs & derivatives; Curcumin - chemistry; Disease Models, Animal; DNA-Binding Proteins - genetics; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Gene Knockdown Techniques; Heat Shock Transcription Factors; Humans; Medicin och hälsovetenskap; Mice; Muscular Disorders, Atrophic - drug therapy; Muscular Disorders, Atrophic - genetics; Muscular Disorders, Atrophic - pathology; NF-E2-Related Factor 1 - genetics; NF-E2-Related Factor 2 - genetics; Oxidative Stress - drug effects; Peptides - genetics; Proteasome Endopeptidase Complex - drug effects; Protein Aggregation, Pathological - genetics; Protein Folding - drug effects; Receptors, Androgen - genetics; Signal Transduction - drug effects; Small Molecule Libraries - administration & dosage; Transcription Factors - genetics; Trinucleotide Repeat Expansion - genetics
• DOI: 10.1093/hmg/ddw073
• ISSN: 0964-6906; 1460-2083

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.