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

• Published in: Journal of neurochemistry 2019-01, Vol.148 (1), p.8-28
• Main Authors: Matos, Carlos A., Almeida, Luís Pereira, Nóbrega, Clévio
• Format: Article
• Language: English
• Subjects: Animal models; Ataxia; Ataxin; ataxin‐3; Autophagy; Gene therapy; Machado-Joseph disease; Mitochondria; Mutation; neurodegeneration; Pathogenesis; Phagocytosis; Pharmacology; Proteins; Proteolysis; therapeutic strategies; Transcription
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14541

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. The complex cascade of molecular and cellular events underlying Machado–Joseph disease, also known as spinocerebellar ataxia type 3 (SCA3), contains several opportunities for therapeutic intervention. Gene therapy and pharmacological approaches aiming at decreasing the formation of toxic ataxin‐3 (atxn3) species or at counteracting the disruption of cellular systems that are crucial for cell function and survival demonstrate promising ameliorating effects in cellular and animal models.