Neurobiology of Disease (Apr 2024)
Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease
- Mafalda Raposo,
- Jeannette Hübener-Schmid,
- Rebecca Tagett,
- Ana F. Ferreira,
- Ana Rosa Vieira Melo,
- João Vasconcelos,
- Paula Pires,
- Teresa Kay,
- Hector Garcia-Moreno,
- Paola Giunti,
- Magda M. Santana,
- Luis Pereira de Almeida,
- Jon Infante,
- Bart P. van de Warrenburg,
- Jeroen J. de Vries,
- Jennifer Faber,
- Thomas Klockgether,
- Nicolas Casadei,
- Jakob Admard,
- Ludger Schöls,
- Olaf Riess,
- Maria do Carmo Costa,
- Manuela Lima
Affiliations
- Mafalda Raposo
- IBMC - Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal; Correspondence to: Mafalda Raposo, Instituto de Investigação e Inovação em Saúde (i3S), Rua Alfredo Allen, 208 4200-135 Porto, Portugal.
- Jeannette Hübener-Schmid
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany; Correspondence to: Jeannette Hübener-Schmid, Institute of Medical Genetics and Applied Genomics, Nägelestraße, 572074 Tübingen, Germany.
- Rebecca Tagett
- Bioinformatics Core, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
- Ana F. Ferreira
- Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal
- Ana Rosa Vieira Melo
- Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal
- João Vasconcelos
- Serviço de Neurologia, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal
- Paula Pires
- Serviço de Neurologia, Hospital do Santo Espírito da Ilha Terceira, Angra do Heroísmo, Portugal
- Teresa Kay
- Serviço de Genética Clínica, Hospital D. Estefânia, Lisboa, Portugal
- Hector Garcia-Moreno
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
- Paola Giunti
- Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; Department of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
- Magda M. Santana
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Coimbra, Portugal
- Luis Pereira de Almeida
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra (FFUC), Coimbra, Portugal
- Jon Infante
- Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain
- Bart P. van de Warrenburg
- Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, the Netherlands
- Jeroen J. de Vries
- Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Jennifer Faber
- Department of Neurology, University Hospital Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Thomas Klockgether
- Department of Neurology, University Hospital Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Nicolas Casadei
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; NGS Competence Center Tübingen, Tübingen, Germany
- Jakob Admard
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; NGS Competence Center Tübingen, Tübingen, Germany
- Ludger Schöls
- Department for Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Olaf Riess
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany; NGS Competence Center Tübingen, Tübingen, Germany
- Maria do Carmo Costa
- Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Correspondence to: Maria do Carmo Costa, Ph.D, Department of Neurology, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 4027109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
- Manuela Lima
- Faculdade de Ciências e Tecnologia, Universidade dos Açores, Ponta Delgada, Portugal; Correspondence to: Manuela Lima, Faculdade de Ciências e Tecnologia, Universidade dos Açores, Rua Mãe de Deus, N.13, 9500-321 Ponta Delgada, Portugal.
- Journal volume & issue
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Vol. 193
p. 106456
Abstract
Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3–251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3–208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3–251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3–214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies.
