PET imaging reveals early and progressive dopaminergic deficits after intra-striatal injection of preformed alpha-synuclein fibrils in rats

Abstract Alpha-synuclein (a-syn) can aggregate and form toxic oligomers insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal bodies a major pathological characteristic Parkinson's disease (PD). These fibrillar structures act as seeds accelerate aggregation monomeric a-syn. Indeed, recent studies show that injection preformed a-syn (PFF) into rodent brain induce endogenous resulting in neuronal dysfunction eventual cell death. We injected 8 ?g murine PFF, or soluble right striatum rats. The animals were monitored behaviourally using cylinder test, measures paw asymmetry, corridor task lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 22 weeks [11C]DTBZ, marker vesicular monoamine 2 transporter (VMAT2), 15 [11C]UCB-J, synaptic SV2A protein nerve terminals. Histology at three time points antibodies against dopaminergic markers, aggregated a-syn, MHCII evaluate immune response. While PFF caused only mild behavioural changes, [11C]DTBZ showed significant progressive decrease VMAT2 binding ipsilateral striatum. This accompanied by small [11C]UCB-J same area. addition, our histological analysis revealed gradual spread misfolded pathology areas anatomically connected became bilateral with time. striatal resulted unilateral degeneration dopamine terminals, an early sustained presence positive ramified microglia substantia nigra. Our study shows injections prior death be detected PET. confirm intrastriatal PFFs provides model loss function neuroinflammation, found human PD.