{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:38:40Z","timestamp":1785429520455,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,27]]},"group-title":"Neuroscience","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS120331"],"award-info":[{"award-number":["R01NS120331"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["3R01NS120331-05S1"],"award-info":[{"award-number":["3R01NS120331-05S1"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00cvnc278","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009797","name":"Barrow Neurological Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009797","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CTR057001"],"award-info":[{"award-number":["CTR057001"]}],"id":[{"id":"https:\/\/ror.org\/01smpj292","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the\n                  <jats:italic>C9ORF72<\/jats:italic>\n                  (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p&lt;0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including\n                  <jats:italic>KALRN<\/jats:italic>\n                  and\n                  <jats:italic>STMN2,<\/jats:italic>\n                  providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.\n                <\/jats:p>","DOI":"10.64898\/2026.07.26.740405","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T16:20:19Z","timestamp":1785169219000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in\n                  <i>C9ORF72<\/i>\n                  -Frontotemporal Dementia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2621-2866","authenticated-orcid":false,"given":"Ashton M.","family":"Spillman","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA"},{"name":"Interdisciplinary Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2717-7573","authenticated-orcid":false,"given":"Eric B.","family":"Alsop","sequence":"additional","affiliation":[{"name":"Bioinnovation and Genome Sciences, Translational Genomics Research Institute, Phoenix, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2742-4033","authenticated-orcid":false,"given":"Lauren M.","family":"Gittings","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystine","family":"Garcia-Mansfield","sequence":"additional","affiliation":[{"name":"Early Detection and Prevention, Translational Genomics Research Institute, Phoenix, AZ, USA"},{"name":"Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4024-3368","authenticated-orcid":false,"given":"Ignazio","family":"Piras","sequence":"additional","affiliation":[{"name":"Bioinnovation and Genome Sciences, Translational Genomics Research Institute, Phoenix, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5796-5167","authenticated-orcid":false,"given":"Anna","family":"Bonfitto","sequence":"additional","affiliation":[{"name":"Bioinnovation and Genome Sciences, Translational Genomics Research Institute, Phoenix, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa N.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Early Detection and Prevention, Translational Genomics Research Institute, Phoenix, AZ, USA"},{"name":"Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8365-9916","authenticated-orcid":false,"given":"Ritin","family":"Sharma","sequence":"additional","affiliation":[{"name":"Early Detection and Prevention, Translational Genomics Research Institute, Phoenix, AZ, USA"},{"name":"Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim R.","family":"Preller","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7390-9918","authenticated-orcid":false,"given":"Matthew","family":"Huentelman","sequence":"additional","affiliation":[{"name":"Bioinnovation and Genome Sciences, Translational Genomics 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