Machado-Joseph disease (MJD) is a neurodegenerative disorder, caused by an abnormal expansion of CAG trinucleotide repeats in the disease-causing gene. This mutation leads to an abnormal polyglutamine tract in the protein ataxin-3, resulting in formation of mutant ataxin-3 aggregates. Despite several attempts to develop a therapeutic option for MJD, currently there are no available therapies capable of delaying or stopping disease progression. Recently, our group reported that reducing the expression levels of mutant ataxin-3 lead to a mitigation of several MJD-related behavior and neuropathological abnormalities. Aiming a more rapid translation to the human clinics, in this study we investigate a pharmacological inhibitor of translation - cordycepin - in several preclinical models. We found that cordycepin treatment significantly reduced: i) the levels of mutant ataxin-3; ii) the neuropathological abnormalities in a lentiviral mouse model; iii) the motor and neuropathological deficits in a transgenic mouse model and iv) the number of ubiquitin aggregates in a human neural model. We hypothesize that the effect cordycepin is mediated by the increase of phosphorylated AMPK levels, which is accompanied by a reduction in the global translation levels and by a significant activation of the autophagy pathway. Overall, this study suggests that cordycepin might constitute an effective and safe therapeutic approach for MJD, and probably for the other polyglutamine diseases.

Machado–Joseph disease or spinocerebellar ataxia type 3 is an inherited neurodegenerative disease associated with an abnormal glutamine over-repetition within the ataxin-3 protein. This mutant ataxin-3 protein affects several cellular pathways, leading to neuroinflammation and neuronal death in specific brain regions resulting in severe clinical manifestations. Presently, there is no therapy able to modify the disease progression. Nevertheless, anti-inflammatory pharmacological intervention has been associated with positive outcomes in other neurodegenerative diseases. Thus, the present work aimed at investigating whether ibuprofen treatment would alleviate Machado–Joseph disease. We found that ibuprofen-treated mouse models presented a significant reduction in the neuroinflammation markers, namely Il1b and TNFa mRNA and IKB-α protein phosphorylation levels. Moreover, these mice exhibited neuronal preservation, cerebellar atrophy reduction, smaller mutant ataxin-3 inclusions and motor performance improvement. Additionally, neural cultures of Machado–Joseph disease patients’ induced pluripotent stem cells-derived neural stem cells incubated with ibuprofen showed increased levels of neural progenitors proliferation and synaptic markers such as MSI1, NOTCH1 and SYP. These findings were further confirmed in ibuprofen-treated mice that display increased neural progenitor numbers (Ki67 positive) in the subventricular zone. Furthermore, interestingly, ibuprofen treatment enhanced neurite total length and synaptic function of human neurons. Therefore, our results indicate that ibuprofen reduces neuroinflammation and induces neuroprotection, alleviating Machado–Joseph disease-associated neuropathology and motor impairments. Thus, our findings demonstrate that ibuprofen treatment has the potential to be used as a neuroprotective therapeutic approach in Machado–Joseph disease.

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