Neuroprotective effects of creatine in the CMVMJD135 mouse model of Spinocerebellar Ataxia type 3

Background and Objective: Mitochondrial dysfunction has been implicated in several neurodegenerative diseases. Creatine administration increases concentration of the energy buffer phosphocreatine, exerting protective effects in the brain. We evaluate whether a creatine‐enriched diet would be beneficial for a mouse model of spinocerebellar ataxia type 3, a genetically defined neurodegenerative disease for which no treatment is available. Methods: We performed 2 independent preclinical trials using the CMVMJD135 mouse model (treating 2 groups of animals with different disease severity) and wild‐type mice, to which 2% creatine was provided for 19 (preclinical trial 1) or 29 (preclinical trial 2) weeks, starting at a presymptomatic age. Motor behavior was evaluated at several time points from 5 to 34 weeks of age, and neuropathological studies were performed at the end of each trial. Results: Creatine supplementation led to an overall improvement in the motor phenotype of CMVMJD135 mice in both trials, rescuing motor balance and coordination and also restored brain weight, mitigated astrogliosis, and preserved Calbindin‐positive cells in the cerebellum. Moreover, a reduction of mutant ataxin‐3 aggregates occurred despite maintained steady‐state levels of the protein and the absence of autophagy activation. Creatine treatment also restored the expression of the mitochondrial mass marker Porin and reduced the expression of antioxidant enzymes Heme oxygenase 1 (HO1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1), suggesting a beneficial effect at the level of mitochondria and oxidative stress. Conclusions: Creatine slows disease progression and improves motor dysfunction as well as ameliorates neuropathology of the CMVMJD135 animals, supporting this as a useful strategy to slow the progression of spinocerebellar ataxia type 3.This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by European Regional Development Fund funds, through the Competitiveness Factors Operational Programme, and by National funds, through the Foundation for Science and Technology, under the scope of the project POCI-01-0145-FEDER-007038 and through the project POCI-01-0145-FEDER016818 (PTDC/NEU-NMC/3648/2014) and fellowships (SFRH/BD/78388/2011 to S. D-S., SFRH/BD/51059/2010 to A.N.C., SFRH/BPD/91562/2012 to A.S-F., SFRH/BD/51992/2012 to C.S-C, SFRH/BD/88932/2012 to J.M.S.).