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Polyglutamine-Independent Features in Ataxin-3 Aggregation and Pathogenesis of Machado-Joseph Disease

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Polyglutamine Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1049))

Abstract

The expansion of a trinucleotide (CAG) repeat, translated into a polyglutamine expanded sequence in the protein encoded by the MJD gene, was identified over 20 years ago as the causative mutation in a severe neurodegenerative disorder originally diagnosed in individuals of Portuguese ancestry. This incapacitating disease, called Machado-Joseph disease or spinocebellar ataxia type 3, is integrated into a larger group of neurodegenerative disorders—the polyglutamine expansion disorders—caused by extension of a CAG repeat in the coding sequence of otherwise unrelated genes. These diseases are generally linked with the appearance of intracellular inclusions , which despite having a controversial role in disease appearance and development represent a characteristic common fingerprint in all polyglutamine-related disorders. Although polyglutamine expansion is an obvious trigger for neuronal dysfunction, the role of the different domains of these complex proteins in the function and aggregation properties of the carrier proteins is being uncovered in recent studies. In this review the current knowledge about the structural and functional features of full-length ataxin-3 protein will be discussed. The intrinsic conformational dynamics and interplay between the globular and intrinsically disordered regions of ataxin-3 will be highlighted, and a perspective picture of the role of known ataxin-3 post-translational modifications on regulating ataxin-3 aggregation and function will be drawn.

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Funding

SM-R lab is funded by (i) National Ataxia Foundation, USA, by (ii) FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and by (iii) Project Norte-01-0145-FEDER-000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). ALC lab is funded by (1) the Brain and Behavior Research Foundation, (2) Fondation Lejeune, and (3) the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000008:BrainHealth 2020, and through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT—Fundação para a Ciência e a Tecnologia, I.P., under project POCI-01-0145-FEDER-007440.

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Authors and Affiliations

  1. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    Ana Luisa Carvalho

  2. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-517, Coimbra, Portugal

    Ana Luisa Carvalho

  3. i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal

    Alexandra Silva & Sandra Macedo-Ribeiro

  4. IBMC—Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135, Porto, Portugal

    Alexandra Silva & Sandra Macedo-Ribeiro

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  1. Ana Luisa Carvalho
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  2. Alexandra Silva
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  3. Sandra Macedo-Ribeiro
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Correspondence to Sandra Macedo-Ribeiro .

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Editors and Affiliations

  1. Department of Biomedical Sciences and Medicine; Centre for Biomedical Research and Algarve Biomedical Center, University of Algarve, Faro, Portugal

    Clévio Nóbrega

  2. Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Luís Pereira de Almeida

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Carvalho, A.L., Silva, A., Macedo-Ribeiro, S. (2018). Polyglutamine-Independent Features in Ataxin-3 Aggregation and Pathogenesis of Machado-Joseph Disease. In: Nóbrega, C., Pereira de Almeida, L. (eds) Polyglutamine Disorders. Advances in Experimental Medicine and Biology, vol 1049. Springer, Cham. https://doi.org/10.1007/978-3-319-71779-1_14

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