Early synaptic dysfunction induced by \u03b1-synuclein in a rat model of Parkinson\u2019s disease

Jenny-Ann Phan,Albert Gjedde,Anne M Landau,Justyna Zareba-Paslawska,Kathrine Stokholm,Kim Vang,Marina Romero-Ramos,Steen Jakobsen

doi:10.1038/s41598-017-06724-9

Abstract

Evidence suggests that synapses are affected first in Parkinson’s disease (PD). Here, we tested the claim that pathological accumulation of α-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human α-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve α-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), [11C]dihydrotetrabenazine (DTBZ). Animals overexpressing α-synuclein had progressive motor impairment and, 12 weeks post-surgery, showed asymmetric in vivo striatal DTBZ binding. The PET images matched ligand binding in post-mortem 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 α-synuclein was observed in dopaminergic terminals, in dystrophic swellings that resembled axonal spheroids and contained mitochondria and vesicular proteins. In conclusion, pathological α-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.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized mainly by progressive loss of dopaminergic neurons from substantia nigra (SN)
We tested the hypothesis that synaptic changes occur before prominent cell loss in a rat model of hemi-parkinsonism in which we locally overexpressed human aggregated α-synuclein (ASYN) by unilateral injection of rAAV2/6-ASYN
We show here that elevated expression of human ASYN in the absence of neuronal loss is sufficient to induce hemi-parkinsonism in animals and that the changes are detected in vivo by non-invasive positron emission tomography (PET)

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized mainly by progressive loss of dopaminergic neurons from substantia nigra (SN). Locus duplication is linked to sporadic PD with late onset, slow disease progression, and absence of prominent cognitive decline[2], while SNCA triplication is linked to an aggressive phenotype, characterized by earlier onset, more extensive ASYN deposition, and more severe motor symptoms[3]. These findings imply that clinical features depend on the degree of SNCA gene expression. Models as transgenic animals with overexpression of ASYN show neuronal dysfunction in the absence of cell loss, including motor defects, electrophysiological changes in basal ganglia, and variability of dopamine release[6]. The model is the result of a unique approach to the modulation of the neurodegenerative process responsible for the ASYN-induced neuropathology with and without loss of cells[13]

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