{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:48:40Z","timestamp":1768506520840,"version":"3.49.0"},"posted":{"date-parts":[[2023,4,9]]},"group-title":"Neuroscience","reference-count":37,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the\n                  <jats:italic>ATXN3<\/jats:italic>\n                  gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD, and to evaluate if expression alterations of specific apoptosis genes\/proteins could be used as transcriptional biomarkers of disease, the levels of\n                  <jats:italic>BCL2, BAX<\/jats:italic>\n                  and\n                  <jats:italic>TP53<\/jats:italic>\n                  and the\n                  <jats:italic>BCL2<\/jats:italic>\n                  \/\n                  <jats:italic>BAX<\/jats:italic>\n                  ratio, an indicator of susceptibility to apoptosis, were assessed in blood and\n                  <jats:italic>post-mortem<\/jats:italic>\n                  brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood\n                  <jats:italic>BCL2<\/jats:italic>\n                  transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood\n                  <jats:italic>BAX<\/jats:italic>\n                  transcripts and decreased\n                  <jats:italic>BCL2<\/jats:italic>\n                  \/\n                  <jats:italic>BAX<\/jats:italic>\n                  ratio are associated with earlier onset, indicating a possible association with MJD pathogenesis.\n                  <jats:italic>Post-mortem<\/jats:italic>\n                  MJD brains show increased\n                  <jats:italic>BCL2<\/jats:italic>\n                  \/\n                  <jats:italic>BAX<\/jats:italic>\n                  transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2\/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood\n                  <jats:italic>BCL2<\/jats:italic>\n                  and\n                  <jats:italic>TP53<\/jats:italic>\n                  transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood\n                  <jats:italic>BCL2, BAX<\/jats:italic>\n                  , and\n                  <jats:italic>TP53<\/jats:italic>\n                  transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue dependent behavior is partially replicated in a MJD mouse model.\n                <\/jats:p>","DOI":"10.1101\/2023.04.09.536069","type":"posted-content","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T01:00:14Z","timestamp":1681088414000},"source":"Crossref","is-referenced-by-count":0,"title":["Tissue-specific vulnerability to apoptosis in Machado-Joseph disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-3364","authenticated-orcid":false,"given":"Ana F.","family":"Ferreira","sequence":"first","affiliation":[]},{"given":"Mafalda","family":"Raposo","sequence":"additional","affiliation":[]},{"given":"Emily D.","family":"Shaw","sequence":"additional","affiliation":[]},{"given":"Naila S.","family":"Ashraf","sequence":"additional","affiliation":[]},{"given":"Filipa","family":"Medeiros","sequence":"additional","affiliation":[]},{"given":"Maria de F\u00e1tima","family":"Brilhante","sequence":"additional","affiliation":[]},{"given":"Matthew","family":"Perkins","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Vasconcelos","sequence":"additional","affiliation":[]},{"given":"Teresa","family":"Kay","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8466-4864","authenticated-orcid":false,"given":"Maria","family":"do Carmo Costa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-3273","authenticated-orcid":false,"given":"Manuela","family":"Lima","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2023041205000587000_2023.04.09.536069v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0074-3"},{"key":"2023041205000587000_2023.04.09.536069v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1194-221"},{"key":"2023041205000587000_2023.04.09.536069v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2011.11.006"},{"key":"2023041205000587000_2023.04.09.536069v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e3282f7673d"},{"key":"2023041205000587000_2023.04.09.536069v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-35"},{"key":"2023041205000587000_2023.04.09.536069v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00714"},{"key":"2023041205000587000_2023.04.09.536069v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25297"},{"key":"2023041205000587000_2023.04.09.536069v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1069-x"},{"key":"2023041205000587000_2023.04.09.536069v1.9","doi-asserted-by":"publisher","DOI":"10.1101\/19011882"},{"key":"2023041205000587000_2023.04.09.536069v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.144"},{"key":"2023041205000587000_2023.04.09.536069v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.152"},{"key":"2023041205000587000_2023.04.09.536069v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2017.04.005"},{"key":"2023041205000587000_2023.04.09.536069v1.13","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25264"},{"key":"2023041205000587000_2023.04.09.536069v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1331-2"},{"key":"2023041205000587000_2023.04.09.536069v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-013-8596-2"},{"key":"2023041205000587000_2023.04.09.536069v1.16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1954-20.2021"},{"key":"2023041205000587000_2023.04.09.536069v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26238"},{"key":"2023041205000587000_2023.04.09.536069v1.18","unstructured":"Raposo, M. 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