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Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats.

Overview

Authors: Marianna Naki1,2, Fedon-Giasin Kattan1, Marina Pantazopoulou3, Sissy Skea4, Dimitrios Zisis5, Eleftherios Pilalis5, Maria Fouka3, Effrosyni Koronaiou3, Christos Fotis4, Olaf Riess6, Aristotelis Chatziioannou5,7, Leonidas G Alexopoulos4,8, Leonidas Stefanis3,9, Epaminondas Doxakis1
ORCID iDs: Epaminondas Doxakis
  1. Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527 Greece
  2. Department of Physiology, National and Kapodistrian University of Athens (NKUA), Athens, 11527 Greece
  3. Center of Clinical Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527 Greece
  4. Protavio Ltd, Demokritos Science Park, Agia Paraskevi, 15341 Greece
  5. e-NIOS Applications PC, Kallithea, 17671 Greece
  6. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, 72076 Germany
  7. Centers of Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, 11527 Greece
  8. Biomedical Systems Laboratory, National Technical University of Athens, Athens, 15780 Greece
  9. First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens, 11528 Greece
Institutions: National and Kapodistrian University of Athens (Greece); Biomedical Research Foundation of the Academy of Athens (Greece); National Centre of Scientific Research "Demokritos" (Greece); University of Tübingen (Germany); Academy of Athens (Greece); National Technical University of Athens (Greece)
Journal: Translational neurodegeneration, volume 15, issue 1, article 47
Dates: received 5 January 2026; accepted 28 July 2026; published online 16 September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s40035-026-00577-x · PMID 42750047 · PMCID PMC13579807 · OpenAlex W7213341094
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), rat (organism), Parkinson's (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Machine learning
Keywords: Alpha-synuclein (SNCA), Parkinson's disease, Antisense oligonucleotide, BAC transgenic rat, 3′UTR targeting, Neuroinflammation, Prodromal intervention
MeSH: 3' Untranslated Regions*, alpha-Synuclein*, Brain*, Oligonucleotides, Antisense*, Parkinson Disease*, Animals, Disease Models, Animal, Humans, Male, Rats, Rats, Transgenic (* major topic)
Topic: Parkinson's Disease Mechanisms and Treatments (Neurology, Medicine), according to OpenAlex
Funding: Michael J. Fox Foundation for Parkinson's Research (16186); Greek General Secretariat for Research and Innovation (Τ2EDK-01291)
Citations: not cited yet (Europe PMC); 69 references in the paper

Abstract

Background: Alpha-synuclein accumulation contributes to Parkinson’s disease (PD), and lowering α-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 SNCA locus.

Methods: BAC-hSNCA rats were treated at an early stage, when human α-synuclein is elevated, but striatal dopamine content remains largely preserved. A single intracerebroventricular dose of an ASO targeting human SNCA 3′UTR (SNCA ASO3.0) was administered, and outcomes were assessed 45 days later by isoform-specific RT-qPCR, immunoblotting of soluble and detergent-insoluble α-synuclein species, bulk RNA-seq across selected regions, multiplex cytokine profiling, phospho-kinase assays, neurotransmitter quantification, and behavioral testing.

Results: SNCA ASO3.0 reduced human SNCA mRNA and multiple α-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.

Conclusions: Partial suppression of human α-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 α-synuclein-lowering interventions in synucleinopathies.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40035-026-00577-x.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Data availability

The RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) repository with the dataset identifier GSE293775. All other data are provided in the article and Supplementary Information.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 7 keywords, 11 MeSH terms, 2 funders, 68 references.

Cite

This paper

Naki, M., Kattan, F.-G., Pantazopoulou, M., Skea, S., Zisis, D., Pilalis, E., Fouka, M., Koronaiou, E., Fotis, C., Riess, O., Chatziioannou, A., Alexopoulos, L. G., Stefanis, L., & Doxakis, E. (2026). Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats. Translational neurodegeneration, 15(1), 47. https://doi.org/10.1186/s40035-026-00577-x

BibTeX

@article{naki2026brain,
author = {Naki, Marianna and Kattan, Fedon-Giasin and Pantazopoulou, Marina and Skea, Sissy and Zisis, Dimitrios and Pilalis, Eleftherios and Fouka, Maria and Koronaiou, Effrosyni and Fotis, Christos and Riess, Olaf and Chatziioannou, Aristotelis and Alexopoulos, Leonidas G and Stefanis, Leonidas and Doxakis, Epaminondas},
title = {{Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats}},
journal = {Translational neurodegeneration},
year = {2026},
month = sep,
volume = {15},
number = {1},
pages = {47},
publisher = {BMC},
issn = {2047-9158},
doi = {10.1186/s40035-026-00577-x},
url = {https://doi.org/10.1186/s40035-026-00577-x},
pmid = {42750047},
pmcid = {PMC13579807}
}

RIS

TY - JOUR
AU - Naki, Marianna
AU - Kattan, Fedon-Giasin
AU - Pantazopoulou, Marina
AU - Skea, Sissy
AU - Zisis, Dimitrios
AU - Pilalis, Eleftherios
AU - Fouka, Maria
AU - Koronaiou, Effrosyni
AU - Fotis, Christos
AU - Riess, Olaf
AU - Chatziioannou, Aristotelis
AU - Alexopoulos, Leonidas G
AU - Stefanis, Leonidas
AU - Doxakis, Epaminondas
TI - Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats
T2 - Translational neurodegeneration
J2 - Transl Neurodegener
PY - 2026
DA - 2026/09/16
VL - 15
IS - 1
SP - 47
SN - 2047-9158
PB - BMC
DO - 10.1186/s40035-026-00577-x
UR - https://doi.org/10.1186/s40035-026-00577-x
LA - en
ER -

CSL-JSON

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