Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice
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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BibTeX
@article{razquin2026locus,
title = {{Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice}},
author = {Jone Razquin and Laura de las Heras-García and Andrea Vaquero-Rodríguez and Sara Fernández-Roqueñí and Gloria González-Aseguinolaza and Edgar Soria-Gómez and Jérôme Baufreton and Harkaitz Bengoetxea and Leticia Abecia and Jorge Ortega and Naiara Ortuzar and Cristina Miguélez},
journal = {Npj Parkinson's Disease},
year = {2026},
month = jun,
doi = {10.1038/s41531-026-01420-w},
url = {https://hal.science/hal-05798265v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice
AU - Jone Razquin
AU - Laura de las Heras-García
AU - Andrea Vaquero-Rodríguez
AU - Sara Fernández-Roqueñí
AU - Gloria González-Aseguinolaza
AU - Edgar Soria-Gómez
AU - Jérôme Baufreton
AU - Harkaitz Bengoetxea
AU - Leticia Abecia
AU - Jorge Ortega
AU - Naiara Ortuzar
AU - Cristina Miguélez
PY - 2026
DA - 2026/06/08
JO - Npj Parkinson's Disease
DO - 10.1038/s41531-026-01420-w
UR - https://hal.science/hal-05798265v1
AB - 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.
SN - 2373-8057
ER -