From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation

  • Jorge Diogo Da Silva
  • Andreia Teixeira-Castro
  • Patrícia MacielEmail author


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.


Spinocerebellar ataxia type 3 Machado-Joseph disease Ataxin-3 Neurodegeneration Molecular pathogenesis Therapeutic advances 



The authors thank all the members of the Maciel lab for their helpful tips and discussion. This work was funded by the European Regional Development Fund (FEDER), through the Competitiveness Internationalization Operational Programme (POCI), and by national funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-0 31987. Moreover, the work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER (project NORTE-01-0145-FEDER-000013). A fellowship supporting the development of this work was attributed by FCT to J. D. Da S. (PD/BD/128074/2016).

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Jorge Diogo Da Silva
    • 1
    • 2
  • Andreia Teixeira-Castro
    • 1
    • 2
  • Patrícia Maciel
    • 1
    • 2
    Email author
  1. 1.Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryBraga/GuimarãesPortugal

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