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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:p>Synaptic loss and dendritic degeneration are common pathologies in several neurodegenerative diseases characterized by progressive cognitive and\/or motor decline, such as Alzheimer\u2019s disease (AD) and frontotemporal dementia\/amyotrophic lateral sclerosis (FTD\/ALS). An essential regulator of neuronal health, the cAMP-dependent transcription factor CREB positively regulates synaptic growth, learning, and memory. Phosphorylation of CREB by protein kinase A (PKA) and other cellular kinases promotes neuronal survival and maturation via transcriptional activation of a wide range of downstream target genes. CREB pathway dysfunction has been strongly implicated in AD pathogenesis, and recent data suggest that impaired CREB activation may contribute to disease phenotypes in FTD\/ALS as well. However, the mechanisms behind reduced CREB activity in FTD\/ALS pathology are not clear. In this study, we found that cortical-like neurons derived from iPSC lines carrying the hexanucleotide repeat expansion in the C9ORF72 gene, a common genetic cause of FTD\/ALS, displayed a diminished activation of CREB, resulting in decreased dendritic and synaptic health. Importantly, we determined such impairments to be mechanistically linked to an imbalance in the ratio of regulatory and catalytic subunits of the CREB activator PKA and to be conserved in C9-ALS patient\u2019s postmortem tissue. Modulation of cAMP upstream of this impairment allowed for a rescue of CREB activity and an amelioration of dendritic morphology and synaptic protein levels. Our data elucidate the mechanism behind early CREB pathway dysfunction and discern a feasible therapeutic target for the treatment of FTD\/ALS and possibly other neurodegenerative diseases.<\/jats:p>","DOI":"10.1073\/pnas.2406998121","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T12:21:54Z","timestamp":1732623714000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Early disruption of the CREB pathway drives dendritic morphological alterations in FTD\/ALS cortical neurons"],"prefix":"10.1073","volume":"121","author":[{"given":"Michelle","family":"Jean Gregoire","sequence":"first","affiliation":[{"name":"Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881"},{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Sirtori","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liviana","family":"Donatelli","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881"},{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Morgan Potts","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881"},{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Collins","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881"},{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielo","family":"Zamor","sequence":"additional","affiliation":[{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natallia","family":"Katenka","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Statistics, University of Rhode Island, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8329-3467","authenticated-orcid":false,"given":"Claudia","family":"Fallini","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, University of Rhode Island, Kingston, RI 02881"},{"name":"Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881"},{"name":"George and Anne Ryan Institute for Neuroscience, Kingston, RI 02881"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00042"},{"key":"e_1_3_4_2_2","first-page":"1","article-title":"Divergence, convergence, and therapeutic implications: A cell biology perspective of C9ORF72-ALS\/FTD","volume":"15","author":"Tang X.","year":"2020","unstructured":"X. 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