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...

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Autores principales:	Jenny-Ann Phan, Kathrine Stokholm, Justyna Zareba-Paslawska, Steen Jakobsen, Kim Vang, Albert Gjedde, Anne M. Landau, Marina Romero-Ramos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/41225ca7cc2e4bf497ecd7a63170b7db
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spelling	oai:doaj.org-article:41225ca7cc2e4bf497ecd7a63170b7db2021-12-02T12:30:18ZEarly synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease10.1038/s41598-017-06724-92045-2322https://doaj.org/article/41225ca7cc2e4bf497ecd7a63170b7db2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06724-9https://doaj.org/toc/2045-2322Abstract 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.Jenny-Ann PhanKathrine StokholmJustyna Zareba-PaslawskaSteen JakobsenKim VangAlbert GjeddeAnne M. LandauMarina Romero-RamosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jenny-Ann Phan Kathrine Stokholm Justyna Zareba-Paslawska Steen Jakobsen Kim Vang Albert Gjedde Anne M. Landau Marina Romero-Ramos Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease
description	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.
format	article
author	Jenny-Ann Phan Kathrine Stokholm Justyna Zareba-Paslawska Steen Jakobsen Kim Vang Albert Gjedde Anne M. Landau Marina Romero-Ramos
author_facet	Jenny-Ann Phan Kathrine Stokholm Justyna Zareba-Paslawska Steen Jakobsen Kim Vang Albert Gjedde Anne M. Landau Marina Romero-Ramos
author_sort	Jenny-Ann Phan
title	Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease
title_short	Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease
title_full	Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease
title_fullStr	Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease
title_full_unstemmed	Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease
title_sort	early synaptic dysfunction induced by α-synuclein in a rat model of parkinson’s disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/41225ca7cc2e4bf497ecd7a63170b7db
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_version_	1718394392923865088

Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease

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