Unknown

Dataset Information

0

Early synaptic dysfunction induced by α-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 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.

PROVIDER: S-EPMC5526979 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC8576889 | BioStudies
| S-EPMC8698691 | BioStudies
| S-EPMC6778064 | BioStudies
2022-02-17 | PXD027786 | Pride
2015-01-01 | S-EPMC4563670 | BioStudies
| S-EPMC3689167 | BioStudies
| S-EPMC5841155 | BioStudies
| S-EPMC8633583 | BioStudies
| S-EPMC7666186 | BioStudies
| S-EPMC4137401 | BioStudies