Abstract
Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. The available treatments only ameliorate symptomatology and do not block disease progression. In this study we find that caloric restriction dramatically rescues the motor incoordination, imbalance and the associated neuropathology in transgenic MJD mice. We further show that caloric restriction rescues SIRT1 levels in transgenic MJD mice, whereas silencing SIRT1 is sufficient to prevent the beneficial effects on MJD pathology. In addition, the re-establishment of SIRT1 levels in MJD mouse model, through the gene delivery approach, significantly ameliorates neuropathology, reducing neuroinflammation and activating autophagy. Furthermore, the pharmacological activation of SIRT1 with resveratrol significantly reduces motor incoordination of MJD mice. The pharmacological SIRT1 activation could provide important benefits to treat MJD patients.
Highlights
Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein
The motor coordination and balance of Tg MJD mice maintained with ad libitum (AL) diet or with Caloric restriction (CR) diet were evaluated by beam walking test, stationary and accelerated rotarod tests, pole test and swimming test
This study indicates that SIRT1 plays an important role in ataxin-3 clearance through the participation on autophagy, because the reduction of mutant ataxin-3 promoted by SIRT1 is reverted when ATG5 is genetically silenced
Summary
Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. In this study we find that caloric restriction dramatically rescues the motor incoordination, imbalance and the associated neuropathology in transgenic MJD mice. The pharmacological activation of SIRT1 with resveratrol significantly reduces motor incoordination of MJD mice. Neurodegeneration is associated with accumulation of the polyglutamine-expanded ataxin-3 (stretch over 55 repeats)[10] in the cells[11,12] To this contributes the cleavage of the mutated protein in toxic fragments, mediated by calpains[13,14,15] and the inefficient activation of autophagy to clear the mutant ataxin-3 (refs 16,17). Emerging data show that this effect is conserved in non-human primates, some controversy subsists[20,21,22]
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