Locus Coeruleus alpha-Synuclein Overexpression Induces Prodromal Parkinsonian Features in Mice

The locus coeruleus is one of the first brain regions to develop -synuclein pathology during the prodromal phase of Parkinsons Disease, contributing significantly to non-motor symptoms such as cognitive decline, mood alterations or sleep disturbances. However, the precise role of the locus coeruleus in the early stages of the disease remains unclear. To address this, we developed and characterized a novel mouse model based on the PRSx8-driven overexpression of human -synuclein in noradrenergic neurons of the locus coeruleus using an adeno-associated viral vector. Animals were assessed at 1 and 3 months post-injection using an integrated battery of histological, behavioural, neurochemical, and electrophysiological analyses. We observed robust accumulation of phosphorylated -synuclein in the locus coeruleus, along with widespread propagation to projection areas, including the hippocampus, prefrontal cortex, and dorsal raphe. Despite the absence of neuronal loss in the locus coeruleus, we identified reduced noradrenergic axonal integrity and marked decreases in both noradrenaline and serotonin levels, highlighting a disruption of neurochemical balance at an early stage. The electrophysiological data revealed transient alterations in the excitability and intrinsic properties of locus coeruleus neurons in a sex-dependent manner, suggesting that -synuclein pathology induces early functional disruption prior to overt neurodegeneration. Behavioural outcomes demonstrated selective cognitive deficits and mild anxiety-like behaviours, while other non-motor functions remained preserved. Importantly, although several pathological and functional alterations were evident in the initial phases, behavioural impairments were also maintained at later time points, indicating that locus coeruleus-driven pathology exerts long-lasting consequences. Interestingly, female mice exhibited colon shortening, providing evidence of a sex-specific pathological process at the level of the gut-brain axis. We believe that this model accurately replicates key prodromal features of Parkinsons disease, demonstrating that -synuclein-induced pathology in the locus coeruleus leads to functional circuit impairment and cognitive decline. Our findings emphasize the locus coeruleus as a critical site of early vulnerability in Parkinsons Disease and underscore the importance of sex as a biological variable influencing disease progression and therapeutic response.