Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice.
Overview
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU,Leioa, Spain
- Department of Neuroscience, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU,Leioa, Spain
- Neurodegenerative Diseases Group, Biobizkaia Health Research Institute, Barakaldo, Spain
- Present Address: Department of Neuroscience, Karolinska Institutet,Stockholm, Sweden
- Univ. Bordeaux, CNRS, IMN, UMR 5293,Bordeaux, France
- Gene Therapy for Rare Diseases Program, DNA & RNA Medicine Division, CIMA, Universidad de Navarra, Pamplona,Navarra, Spain
- Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU,Leioa, Spain
- IKERBASQUE, Basque Foundation for Science,Bilbao, Spain
- Department of Immunology, Microbiology and Parasitology, University of the Basque Country UPV/EHU,Leioa, Spain
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III,Leioa, Spain
- Early Phases of Psychosis Group, Biobizkaia Health Research Institute, Barakaldo, Spain
Abstract
The locus coeruleus is among the earliest brain regions affected by α-synuclein pathology in prodromal Parkinson’s disease, contributing to non-motor symptoms, yet its early pathogenic role remains unclear. We developed a mouse model in which human α-synuclein was selectively overexpressed in noradrenergic locus coeruleus neurons using PRSx8-driven adeno-associated viral vector. Mice were analysed at 1 and 3 months post-injection using histological, behavioural, neurochemical and electrophysiological approaches. Monomeric α-synuclein was localized in the locus coeruleus cell bodies and distributed throughout noradrenergic neuronal projections, while phosphorylated α-synuclein was predominantly confined to the locus coeruleus somata. We also observed reduced noradrenergic axonal density and early decreases in noradrenaline and serotonin levels without neuron loss. In contrast, the dopaminergic system remained unchanged. Electrophysiological recordings revealed transient, sex-dependent alterations in neuronal excitability. At the behavioural level, mice exhibited cognitive deficits and altered innate-emotional behaviour persisting over time. Sex-specific analyses revealed shortening of the colon in females, in the absence of detectable morphological alterations, α-synuclein deposition, or systemic inflammation. This model recapitulates some of the key non-motor Parkinson’s disease features, highlighting the locus coeruleus as a potential target for early intervention.
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Data
Datasets cited
- zenodo:19865488, at Zenodo; found in “Data availability”
Data availability
The datasets generated and analysed during the current study are available in Zenodo repository, https://
Reproduced under the paper's license (CC BY), from the paper cited above.
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 2 keywords, 4 funders, 102 references.
Cite
This paper
Razquin, J., De Las Heras-García, L., Vaquero-Rodríguez, A., Fernández-Roqueñí, S., González-Aseguinolaza, G., Soria-Gómez, E., Baufreton, J., Bengoetxea, H., Abecia, L., Ortega, J. E., Ortuzar, N., & Miguélez, C. (2026). Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice. NPJ Parkinson's disease, 12(1), 225. https://
BibTeX
@article{razquin2026locu
author = {Razquin, Jone and De Las Heras-García, Laura and Vaquero-Rodríguez, Andrea and Fernández-Roqueñí, Sara and González-Aseguinolaza, Gloria and Soria-Gómez, Edgar and Baufreton, Jérôme and Bengoetxea, Harkaitz and Abecia, Leticia and Ortega, Jorge E. and Ortuzar, Naiara and Miguélez, Cristina},
title = {{Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice}},
journal = {NPJ Parkinson's disease},
year = {2026},
month = jun,
volume = {12},
number = {1},
pages = {225},
publisher = {Nature Publishing Group},
issn = {2373-8057},
doi = {10.1038/
url = {https://
pmid = {42259817},
pmcid = {PMC13583003}
}
RIS
TY - JOUR
AU - Razquin, Jone
AU - De Las Heras-García, Laura
AU - Vaquero-Rodríguez, Andrea
AU - Fernández-Roqueñí, Sara
AU - González-Aseguinolaza, Gloria
AU - Soria-Gómez, Edgar
AU - Baufreton, Jérôme
AU - Bengoetxea, Harkaitz
AU - Abecia, Leticia
AU - Ortega, Jorge E.
AU - Ortuzar, Naiara
AU - Miguélez, Cristina
TI - Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice
T2 - NPJ Parkinson's disease
J2 - NPJ Parkinsons Dis
PY - 2026
DA - 2026/
VL - 12
IS - 1
SP - 225
SN - 2373-8057
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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