Alpha-synuclein pathological deposition alters functional homeostasis and connectivity of striatal dopaminergic synapses and results in microglia activation, pathology spreading, muscle stiffness, whole brain atrophy and metabolic changes before producing frank nigral neuron deafferentation

The progressive accumulation of α-synuclein (α-Syn) aggregates is believed to contribute to Parkinson’s disease (PD) pathogenesis. Nevertheless, the earliest pre-degenerative molecular, functional, neuroinflammatory and metabolic changes associated with α-Syn-pathology deposition still need to be disclosed and staged. Here, we investigated these events in a transgenic mouse model of early prodromal PD expressing C-terminally truncated human (1-120 amino acids) α-Syn under the guidance of rat tyrosine hydroxylase (TH) promoter by using two-photon and confocal microscopy, functional and behavioural studies, longitudinal Magnetic Resonance Imaging (MRI) and Positron Emission Tomography plus Computed Tomography (PET-CT) followed by conventional or radiomic analysis. We found that before the onset of frank dopaminergic striatal fibres deafferentation, α-Syn transgenic mice exhibited significant alterations of dopaminergic synapse functional homeostasis and connectivity, accompanied by other widespread brain changes. In particular, we observed early, transient increase of striatal Vesicular Monoamine Transporter 2 (VMAT2) and dopamine transporter (DAT), alterations in striatal dopamine turnover, increase of depolarization-dependent dopamine release and loss of DAT inhibition-related dopamine facilitation. These occurred in the absence of dopamine release deficits and were associated with signs of stiffness without motility impairment. PET-CT confirmed early but transient increase of DAT binding in the dorsal striatum, followed by a significant raise in the neuroinflammation marker [ ¹⁸ F]-VC701 as corroborated by Ionized calcium-binding adaptor molecule 1 (Iba1) immunolabeling. MRI studies evidenced early brain atrophy and volume reduction in different brain areas of transgenic mice. Radiomic-based analysis of [ ¹⁸ F]-FDG-PET-CT revealed significant increasing texture changes supportive of progressive metabolic alterations throughout the brain. Finally, we also observed pathology diffusion in non-catecholaminergic neurons of the motor cortex. Our findings indicate that α-Syn pathology drives early unexpected molecular and connectivity changes at dopaminergic synapses in parallel with pathology spreading, neuroinflammation, widespread brain atrophy and metabolic alterations before leading to the onset of explicit nigrostriatal deafferentation and motility impairment.