Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

Journal of Translational Medicine

Hagar Greif¹  Susana Paixão²  Allyson Trevino-Garcia²  Clévio Nóbrega²  Laetitia S. Gaspar²  Janete Cunha-Santos²  Rui Jorge Nobre²  Magda M. Santana²  Luís Pereira de Almeida²  Teresa Pereira Silva²  Cláudia Cavadas² 

[1] Bioblast Pharma;CNC - Center for Neuroscience and Cell Biology, University of Coimbra;

关键词: Machado-Joseph disease;    Spinocerebellar ataxia type 3;    Polyglutamine disorder;    Trehalose;    Autophagy;   

DOI  :  10.1186/s12967-020-02302-2

来源: DOAJ

【 摘 要 】

Abstract Background Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 aggregation and neuronal degeneration. There is no treatment available to block or delay disease progression. In this work we investigated whether trehalose, a natural occurring disaccharide widely used in food and cosmetic industry, would rescue biochemical, behavioral and neuropathological features of an in vitro and of a severe MJD transgenic mouse model. Methods Two MJD animal models, a lentiviral based and a transgenic model, were orally treated with 2% trehalose solution for a period of 4 and 30 weeks, respectively. Motor behavior (rotarod, grip strength and footprint patterns) was evaluated at different time points and neuropathological features were evaluated upon in-life phase termination. Results Trehalose-treated MJD mice equilibrated for a longer time in the rotarod apparatus and exhibited an improvement of ataxic gait in footprint analysis. Trehalose-mediated improvements in motor behaviour were associated with a reduction of the MJD-associated neuropathology, as MJD transgenic mice treated with trehalose presented preservation of cerebellar layers thickness and a decrease in the size of ataxin-3 aggregates in Purkinje cells. In agreement, an improvement of neuropathological features was also observed in the full length lentiviral-based mouse model of MJD submitted to 2% trehalose treatment. Conclusions The present study suggests trehalose as a safety pharmacological strategy to counteract MJD-associated behavioural and neuropathological impairments.

【 授权许可】

Unknown