Research Award

Luis Pereira de Almeida, PhD

Center for Neurosciences and Cell Biology and Faculty of Pharmacy, University of Coimbra, Portugal
Modulation of autophagy as a novel therapeutic strategy for Machado-Joseph disease

Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) is a genetic neurodegenerative disorder originally described in people of Portuguese descent, and the most common of the dominantly inherited ataxias worldwide. MJD is associated with expansion of the number of CAGs within the coding region of the causative gene - MJD1. The abnormal over-repetition of the CAG trinucleotide is translated into an expanded polyglutamine (polyQ) tract within ataxin-3, a protein involved in deubiquitination. MJD patients have severe clinical manifestations and premature death. Despite important progresses, the mechanisms accounting for neuronal degeneration are still largely unknown and there is no treatment available. So, it is of utmost importance to establish new targets and to develop new strategies to protect from the characteristic neurodegeneration that occurs in MJD.

Recent evidences suggest that autophagy modulates pathological processes that occur in different neurodegenerative diseases. Although autophagy generally prevents neuronal cell death, it plays a protective or detrimental role in neurodegenerative disease depending on the environment. Our recent preliminary results show that in the brain of MJD animal models and also in MJD patients brains there is accumulation of autophagosomes immunoreactive for the LC3 marker of autophagy. This accumulation, resulting from increased autophagosome induction or impaired autophagosome maturation, is associated to an impairment of the autophagic pathway and will contribute to the pathogenesis of MJD. Therefore, the delivery of a regulator of the autophagy pathway represents a strategy toward developing a therapy for Machado Joseph disease. In the present project we propose to evaluate the role of autophagy in MJD, and to evaluate a new therapeutic approach by modulating autophagy through viral gene delivery of beclin-1, a regulator of the autophagy pathway, into the brain of animal models of MJD.

This project is expected to contribute to sort out the pathogenic mechanism of neurodegeneration of MJD, to validate a new therapeutic target – autophagy – and hopefully contribute to the development of a new therapy for MJD.