Locus coeruleus α-synuclein overexpression induces prodromal Parkinsonian features in mice

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.