@article{10902/32938,
year = {2024},
url = {https://hdl.handle.net/10902/32938},
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.},
organization = {Funding: This work is an outcome of ESMI, an EU Joint Programme – Neuro-degenerative Disease Research (JPND) project. The ESMI project was supported through the following funding organisations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Fundaçao para a Ciencia e a Tecnologia (FCT; funding codes JPCOFUND/0002/2015); United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 643417. MR is supported by FCT (CEECIND/03018/2018). AFF and ARVM received PhD fellowships from the FCT (SFRH/BD/121101/2016 and SFRH/BD/129547/2017, respectively). This work was funded by National Funds through FCT, under the project UIDB/04293/2020. Fundo Regional para a Ciˆencia e Tecnologia (FRCT, Governo Regional dos Açores) is currently supporting ESMI in the Azores, under the PRO-SCIENTIA program. NGS sequencing methods were performed with the support of the DFG-funded NGS Competence Center Tübingen (INST 37/1049–1). Bio-informatic analysis was funded by Fundo Regional para a Ciˆencia e Tecnologia (FRCT, Governo Regional dos Açores), under the PRO-SCIENTIA program (ML) and by discretionary funds from the University of Michigan (MCC). MCC is supported by the Heeringa Ataxia Research Fund (University of Michigan). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.
Acknowledgements: The ESMI consortium would like to thank Nina Roy for coordination and managing of the project. We gratefully thank Dr. Aires Raposo for the collaboration on blood collection in Azores islands. Additional members of the European Spinocerebellar Ataxia type 3/ Machado-Joseph Initiative (ESMI) Study Group are listed in Supplementary Material (Table S3) and participated in subject recruitment and acquisition of participants data as well as read and approved the final manuscript.},
publisher = {Elsevier},
publisher = {Neurobiology of Disease, 2024, 193, 106456},
title = {Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease},
author = {Raposo, Mafalda and Hübener-Schmid, Jeannette and Tagett, Rebecca and Ferreira, Ana F. and Vieira Melo, Ana Rosa and Vasconcelos, Joao and Pires, Paula and Kay, Teresa and García-Moreno, Héctor and Giunti, Paola and Santana, Magda M. and Pereira de Almeida, Luis and Infante Ceberio, Jon and Van de Warrenburg, Bart P. and De Vries, Jeroen J. and Faber, Jennifer and Klockgether, Thomas and Casadei, Nicolas and Admard, Jakob},
}