{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:03:34Z","timestamp":1789625014656,"version":"build-2803163510"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Microexons are short exonic sequences of 3\u201330 nucleotides that undergo alternative splicing and have been implicated in several neurodevelopmental disorders. However, their contribution to neurodegenerative diseases remains insufficiently characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed microexon-associated junction usage in the frontal cortex of Parkinson\u2019s disease (PD) patients and in the cerebellum of Spinocerebellar Ataxia Type 3 (SCA3) patients using deep RNA-Sequencing of human postmortem brain tissue and corresponding SH-SY5Y cellular models. Microexon-associated junction usage was quantified based on splice junction reads derived from STAR alignments, followed by statistical testing with false discovery rate (FDR) correction for multiple testing and visualization using Sashimi plots. Selected candidate events in the cellular datasets were assessed by PCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Across all datasets, 19 microexon-associated junction candidate events were identified but did not survive FDR correction. Human brain tissue exhibited substantially more detectable microexons compared to cellular models, which may reflect differences in splicing complexity between differentiated tissue and neuroblastoma-derived cells. While visual inspection suggested that effect sizes were generally small and variable across samples, the majority of microexon-containing genes were expressed in both systems. PCR confirmed detection of the selected microexons but did not validate differences in microexon-associated junction usage between experimental groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings provide an overview of microexon landscapes in PD and SCA3 and an exploratory statistical analysis. Although large and consistent disease-specific patterns of microexon-associated junction usage were not observed, our findings suggest that microexon regulation in neurodegeneration may involve subtle and context-dependent alterations that warrant further investigation in larger cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2026.1872346","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:31:06Z","timestamp":1789623066000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of microexon-associated junction usage in Parkinson\u2019s disease and spinocerebellar Ataxia type 3"],"prefix":"10.3389","volume":"19","author":[{"given":"Kira","family":"Mehnert","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"H\u00fcbener-Schmid","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Department of Life Sciences, Reutlingen University","place":["Reutlingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Admard","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"DFG NGS Competence Center T\u00fcbingen (NCCT), University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav","family":"Lysenkov","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"DFG NGS Competence Center T\u00fcbingen (NCCT), University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Demidov","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrisovalantou","family":"Huridou","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonasz Jeremiasz","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Riess","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"DFG NGS Competence Center T\u00fcbingen (NCCT), University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Casadei","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"DFG NGS Competence Center T\u00fcbingen (NCCT), University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e2350774","DOI":"10.1002\/eji.202350774","article-title":"Actinin-4 controls survival signaling in B cells by limiting the lateral mobility of B-cell antigen receptors","volume":"54","author":"Alsouri","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"ref2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/313545a0","article-title":"Segmental distribution of bithorax complex proteins during Drosophila development","volume":"313","author":"Beachy","year":"1985","journal-title":"Nature"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/7323508","article-title":"Comparative analysis and classification of cassette exons and constitutive exons","volume":"2017","author":"Cui","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1007\/s00415-020-10274-y","article-title":"PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study","volume":"268","author":"Gonsior","year":"2021","journal-title":"J. Neurol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1007\/s12035-021-02610-8","article-title":"A novel SCA3 Knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities especially in oligodendrocytes","volume":"59","author":"Haas","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"18889","DOI":"10.18632\/aging.103935","article-title":"Increased expression of myelin-associated genes in frontal cortex of SNCA overexpressing rats and Parkinson's disease patients","volume":"12","author":"Hentrich","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1016\/j.cell.2014.11.035","article-title":"A highly conserved program of neuronal microexons is misregulated in autistic brains","volume":"159","author":"Irimia","year":"2014","journal-title":"Cell"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/s12276-024-01206-1","article-title":"Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles","volume":"56","author":"Kang","year":"2024","journal-title":"Exp. Mol. 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Disord."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1515\/hsz-2023-0358","article-title":"Structure, function, and recombinant production of EGFL7","volume":"405","author":"McDonald","year":"2024","journal-title":"Biol. Chem."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e12886","DOI":"10.1111\/acel.12886","article-title":"Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging","volume":"18","author":"Neuner","year":"2019","journal-title":"Aging Cell"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e1532","DOI":"10.1002\/wrna.1532","article-title":"Splicing and neurodegeneration: insights and mechanisms","volume":"10","author":"Nik","year":"2019","journal-title":"Wiley Interdiscip. 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Psychiatry"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/genes16070799","article-title":"Expanding the phenotypic Spectrum associated with DPH5-related Diphthamide deficiency","volume":"16","author":"Politano","year":"2025","journal-title":"Genes (Basel)"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"598064","DOI":"10.3389\/fgene.2020.598064","article-title":"Parkinson's disease in Teneurin transmembrane protein 4 (TENM4) mutation carriers","volume":"11","author":"Pu","year":"2020","journal-title":"Front. 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Genet."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-026-03973-8","article-title":"saseR: juggling offsets unlocks RNA-seq tools for fast and scalable differential usage, aberrant splicing and expression retrieval","volume":"27","author":"Segers","year":"2026","journal-title":"Genome Biol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"2574","DOI":"10.3390\/cells11162574","article-title":"Vitamin B12 attenuates changes in phospholipid levels related to oxidative stress in SH-SY5Y cells","volume":"11","author":"Theiss","year":"2022","journal-title":"Cells"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1002\/dvdy.10126","article-title":"Expression of the ankyrin repeat domain 6 gene (Ankrd6) during mouse brain development","volume":"224","author":"Tissir","year":"2002","journal-title":"Dev. Dyn."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e1418","DOI":"10.1002\/wrna.1418","article-title":"Microexons: discovery, regulation, and function","volume":"8","author":"Ustianenko","year":"2017","journal-title":"Wiley Interdiscip. Rev.: RNA"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s00438-025-02299-7","article-title":"Comprehensive study of W06A7.4 and TMEM144 mediated pathways in aging: insights from Caenorhabditis elegans to human","volume":"300","author":"Wang","year":"","journal-title":"Mol. Gen. Genomics."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1002\/mds.30123","article-title":"Mitochondria-related genome-wide Mendelian randomization identifies putatively causal genes for neurodegenerative diseases","volume":"40","author":"Wang","year":"","journal-title":"Mov. Disord."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e2006613","DOI":"10.1371\/journal.pbio.2006613","article-title":"MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis","volume":"16","author":"Xu","year":"2018","journal-title":"PLoS Biol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction","volume":"13","author":"Ye","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2770","DOI":"10.1002\/mds.70039","article-title":"Expanding the autosomal recessive gene Spectrum of Parkinson's disease: a study within the CPD10KGP","volume":"40","author":"Zhao","year":"2025","journal-title":"Mov. 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