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From pathogenesis to novel therapeutics for spinocerebellar ataxia Type 3: Evading potholes on the way to translation

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Resumo:Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in the ATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a realistic perspective on how the translational/clinical research in SCA3 should evolve. This was based on molecular findings, clinical and epidemiological characteristics, studies of proposed treatments in other conditions, and how that information is essential for their (re-)application in SCA3. This review thus aims i) to critically evaluate the current state of research on SCA3, from fundamental to translational and clinical perspectives; ii) to bring up the current key questions that remain unanswered in this disorder; and iii) to provide a frame on how those answers should be pursued.
Autores principais:Da Silva, Jorge Diogo
Outros Autores:Castro, Andreia Cristiana Teixeira; Maciel, P.
Assunto:Animals Ataxin-3 Genetic Therapy Humans Machado-Joseph Disease Protein Biosynthesis Repressor Proteins Spinocerebellar ataxia type 3 Neurodegeneration Molecular pathogenesis Therapeutic advances
Ano:2019
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso restrito
Instituição associada:Universidade do Minho
Idioma:inglês
Origem:RepositóriUM - Universidade do Minho

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