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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["16186"],"award-info":[{"award-number":["16186"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Greek General Secretariat for Research and Innovation","award":["\u03a42EDK-01291"],"award-info":[{"award-number":["\u03a42EDK-01291"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Neurodegener"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Alpha-synuclein accumulation contributes to Parkinson\u2019s disease (PD), and lowering \u03b1-synuclein expression is a candidate disease-modifying approach. The brain-wide pharmacodynamic profile of human-targeting antisense oligonucleotides (ASOs) remains incompletely defined in humanized models that preserve the regulatory architecture of the human\n                      <jats:italic>SNCA<\/jats:italic>\n                      locus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      BAC-h\n                      <jats:italic>SNCA<\/jats:italic>\n                      rats were treated at an early stage, when human \u03b1-synuclein is elevated, but striatal dopamine content remains largely preserved. A single intracerebroventricular dose of an ASO targeting human\n                      <jats:italic>SNCA<\/jats:italic>\n                      3\u2032UTR (SNCA ASO3.0) was administered, and outcomes were assessed 45\u00a0days later by isoform-specific RT-qPCR, immunoblotting of soluble and detergent-insoluble \u03b1-synuclein species, bulk RNA-seq across selected regions, multiplex cytokine profiling, phospho-kinase assays, neurotransmitter quantification, and behavioral testing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SNCA ASO3.0 reduced human\n                      <jats:italic>SNCA<\/jats:italic>\n                      mRNA and multiple \u03b1-synuclein protein species in a regionally graded manner, with the strongest effects in the olfactory bulb and striatum. Bulk RNA-seq identified anatomically distinct transcriptional responses, including synaptic and metabolic pathway shifts in the olfactory bulbs and immune-related enrichment within glial signatures in the striatum and midbrain, without detectable changes in protein levels of glial fibrillary acidic protein or ionized calcium-binding adapter molecule 1. Cytokine profiling showed selective modulation of a subset of analytes, and phospho-kinase assays indicated reduced AKT1S1\/PRAS40 phosphorylation. Striatal dopamine levels were unchanged, whereas the striatal tyrosine hydroxylase level was increased. SNCA ASO3.0 increased locomotor activity and improved exploratory behavior and selected measures of olfactory discrimination.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Partial suppression of human \u03b1-synuclein in a humanized rat model yields region-specific molecular adaptations accompanied by early behavioral changes at a stage preceding overt dopamine depletion. These data provide a framework for evaluating region-resolved consequences of \u03b1-synuclein-lowering interventions in synucleinopathies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00577-x","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:31:08Z","timestamp":1789533068000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3\u2032UTR in BAC-hSNCA rats"],"prefix":"10.1186","volume":"15","author":[{"given":"Marianna","family":"Naki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fedon-Giasin","family":"Kattan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Pantazopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sissy","family":"Skea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Zisis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftherios","family":"Pilalis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fouka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Effrosyni","family":"Koronaiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Fotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Riess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristotelis","family":"Chatziioannou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas G.","family":"Alexopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas","family":"Stefanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1305-0739","authenticated-orcid":false,"given":"Epaminondas","family":"Doxakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"issue":"2","key":"577_CR1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.tins.2022.11.007","volume":"46","author":"M Sharma","year":"2023","unstructured":"Sharma M, Burre J. alpha-Synuclein in synaptic function and dysfunction. 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