Autor(es):
Santana, Magda M. ; Paixão, Susana ; Cunha-Santos, Janete ; Silva, Teresa Pereira ; Trevino-Garcia, Allyson ; Gaspar, Laetitia da Silva ; Nóbrega, Clévio ; Nobre, Rui J. ; Cavadas, Cláudia ; Greif, Hagar ; Almeida, Luís Pereira de
Data: 2020
Identificador Persistente: https://hdl.handle.net/10316/106332
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Machado-Joseph disease; Spinocerebellar ataxia type 3; Polyglutamine disorder; Trehalose; Autophagy; Animals; Ataxin-3; Disease Models, Animal; Mice; Mice, Transgenic; Phenotype; Trehalose; Machado-Joseph Disease
Descrição
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.
This work was funded by BioBlast Pharma, the ERDF through the Regional Operational Program Center 2020, Competitiveness Factors Operational Program (COMPETE 2020) and National Funds through FCT (Foundation for Science and Technology) - SFRH/BD/87404/2012, BrainHealth2020 projects (CENTRO-01-0145-FEDER-000008), ViraVector (CENTRO-01-0145- FEDER-022095), CortaCAGs (POCI-01-0145-FEDER-016719), SpreadSilencing POCI-01-0145-FEDER-029716 and POCI-01-0145-FEDER-007440, as well as the SynSpread, ESMI and ModelPolyQ under the EU Joint Program- Neurodegenerative Disease Research (JPND), the last two co-funded by the European Union H2020 program, GA No. 643417; by National Ataxia Foundation (USA), the American Portuguese Biomedical Research Fund (APBRF) and the Richard Chin and Lily Lock Machado–Joseph Disease Research Fund.
