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.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-01-0145FEDER-022095), CortaCAGs (POCI-01-0145-FEDER-016719), SpreadSilenc‑ing POCI-01-0145-FEDER-029716 and POCI-01-0145-FEDER-007440, as well
as the SynSpread, ESMI and ModelPolyQ under the EU Joint ProgramNeurodegenerative Disease Research (JPND), the last two co-funded bythe 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.info:eu-repo/semantics/publishedVersio

Cavadas, Cláudia

Cunha-Santos, Janete

Gaspar, Laetitia S.

Greif, Hagar

Nobre, Rui Jorge

Nóbrega, Clévio

Paixão, Susana

Pereira de Almeida, Luís

Santana, Magda M.

Silva, Teresa Pereira

Trevino-Garcia, Allyson

Journal of Translational Medicine

English

Universidade do Algarve

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

Estudo Geral

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

Gaspar, Laetitia da Silva

Nobre, Rui J.

Almeida, Luís Pereira de

Trehalose alleviates the phenotype of Machado-Joseph disease mouse models

Sapientia (Univ. do Algarve)

https://sapientia.ualg.pt/bitstream/10400.1/13814/1/s12967-020-02302-2.pdf

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

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Universidade do Algarve

Estudo Geral

Estudo Geral

Sapientia (Univ. do Algarve)