Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease

Abstract

Evidence suggests that synapses are affected first in Parkinson's disease (PD). Here, we tested the claim that pathological accumulation of alpha-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human alpha-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve alpha-synuclein levels sufficient to induce terminal pathology without significant loss of nigral neurons. We tested synaptic disruption in vivo by analyzing motor defects and binding of a positron emission tomography (PET) radioligand to the vesicular monoamine transporter 2, (VMAT2), [C-11] dihydrotetrabenazine (DTBZ). Animals overexpressing alpha-synuclein had progressive motor impairment and, 12 weeks post-surgery, showed asymmetric in vivo striatal DTBZ binding. The PET images matched ligand binding in postmortem tissue, and histological markers of dopaminergic integrity. Histology confirmed the absence of nigral cell death with concomitant significant loss of striatal terminals. Progressive aggregation of proteinase-K resistant and Ser129-phosphorylated alpha-synuclein was observed in dopaminergic terminals, in dystrophic swellings that resembled axonal spheroids and contained mitochondria and vesicular proteins. In conclusion, pathological alpha-synuclein in nigro-striatal axonal terminals leads to early axonal pathology, synaptic disruption, dysfunction of dopaminergic neurotransmission, motor impairment, and measurable change of VMAT2 in the absence of cell loss.