RESUMEN
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.
Asunto(s)
Atrofia Bulboespinal Ligada al X/genética , Curcumina/análogos & derivados , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Trastornos Musculares Atróficos/genética , Factor 1 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/genética , Receptores Androgénicos/genética , Factores de Transcripción/genética , Expansión de Repetición de Trinucleótido/genética , Animales , Atrofia Bulboespinal Ligada al X/tratamiento farmacológico , Atrofia Bulboespinal Ligada al X/patología , Curcumina/administración & dosificación , Curcumina/química , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Técnicas de Silenciamiento del Gen , Factores de Transcripción del Choque Térmico , Humanos , Ratones , Trastornos Musculares Atróficos/tratamiento farmacológico , Trastornos Musculares Atróficos/patología , Estrés Oxidativo/efectos de los fármacos , Péptidos/genética , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Agregación Patológica de Proteínas/genética , Pliegue de Proteína/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/administración & dosificaciónRESUMEN
The antileprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when coadministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.