The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

Aims Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly-inherited ataxia worldwide and is characterised by the accumulation of mutant ataxin-3 (mutATXN3) in different brain regions, leading to neurodegeneration. Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology. Methods The autophagy-enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD-associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients. Results We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up-regulated autophagy through activation of AMPK, which was dependent on the myo-inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study. Conclusions Our data support the autophagy-enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.Fundação para Ciência e Tecnologia; Richard Chin and Lily Lock Machado-Joseph Disease Research Fund; American Portuguese Biomedical Research Fund (APBRF); National Ataxia Foundation (USA); European Union H2020 program, GA No.643417; EU Joint Program - Neurodegenerative Disease Research (JPND); Competitiveness Factors Operational Program (COMPETE 2020); ERDF through the Regional Operational Program Center 2020