Machado-Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an incurable disorder, widely regarded as the most common form of spinocerebellar ataxia in the world. MJD/SCA3 arises from mutation of the ATXN3 gene, but this simple monogenic cause contrasts with the complexity of the pathogenic mechanisms that are currently admitted to underlie neuronal dysfunction and death. The aberrantly expanded protein product - ataxin-3 - is known to aggregate and generate toxic species that disrupt several cell systems, including autophagy, proteostasis, transcription, mitochondrial function and signalling. Over the years, research into putative therapeutic approaches has often been devoted to the development of strategies that counteract disease at different stages of cellular pathogenesis. Silencing the pathogenic protein, blocking aggregation, inhibiting toxic proteolytic processing and counteracting dysfunctions of the cellular systems affected have yielded promising ameliorating results in studies with cellular and animal models. The current review analyses the available studies dedicated to the investigation of MJD/SCA3 pathogenesis and the exploration of possible therapeutic strategies, focusing primarily on gene therapy and pharmacological approaches rooted on the molecular and cellular mechanisms of disease.European Union through the European social fund FEDER through the Competitive Factors Operational Program - COMPETE POPH QREN French Muscular Dystrophy Association (AFM-Telethon) Ataxia UK FEDER through the Competitive Factors Operational Program-COMPETE CENTRO-07-ST24-FEDER-002002 National Funds (PIDDAC) Portuguese Foundation for Science and Technology (FCT) UID/NEU/04539/2013 French Muscular Dystrophy Association (AFM) National Ataxia Foundation (NAF) Richard Chin and Lily Lock MachadoJoseph disease Research Fund BrainHealth 2020 - Deteccao Precoce, Neuromodulacao e Terapias Avancadas para Neuropatologias CENTRO-01-0145-FEDER-000008 Joint call for European Research Project on Rare Diseases E-Rare4/0003/2012