Mafalda Raposo1,2, Conceição Bettencourt3, Patrícia Maciel4,5, Fuying Gao6, Amanda Ramos1,2, Nadiya Kazachkova1,2, João Vasconcelos7, Teresa Kay8, Ana João Rodrigues4,5, Bruno Bettencourt2,9, Jácome Bruges-Armas2,9, Daniel Geschwind6, Giovanni Coppola6, Manuela Lima1,2. 1. Centre of Research in Natural Resources (CIRN), University of the Azores, Ponta Delgada, Portugal. 2. Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal. 3. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. 4. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. 5. ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal. 6. Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA. 7. Department of Neurology, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal. 8. Department of Clinical Genetics, Hospital of D. Estefania, Lisbon, Portugal. 9. Hospital de Santo Espírito da Ilha Terceira, SEEBMO, Angra do Heroísmo, Portugal.
Abstract
BACKGROUND: Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status. METHODS: The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR). RESULTS: Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls. CONCLUSIONS: Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease.
BACKGROUND:Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status. METHODS: The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR). RESULTS: Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls. CONCLUSIONS: Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease.
Authors: Ana F Ferreira; Mafalda Raposo; João Vasconcelos; Maria do Carmo Costa; Manuela Lima Journal: J Mol Neurosci Date: 2019-07-08 Impact factor: 3.444
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Authors: Gabriel Vasata Furtado; Camila Maria de Oliveira; Gabriela Bolzan; Jonas Alex Morales Saute; Maria Luiza Saraiva-Pereira; Laura Bannach Jardim Journal: Genet Mol Biol Date: 2019-06-10 Impact factor: 1.771