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

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Standard

Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease. / Phan, Jenny-Ann; Stokholm, Kathrine; Zareba-Paslawska, Justyna; Jakobsen, Steen; Vang, Kim; Gjedde, Albert; Landau, Anne M.; Romero-Ramos, Marina.

I: Scientific Reports, Bind 7, 6363, 2017.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Phan, J-A, Stokholm, K, Zareba-Paslawska, J, Jakobsen, S, Vang, K, Gjedde, A, Landau, AM & Romero-Ramos, M 2017, 'Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease', Scientific Reports, bind 7, 6363. https://doi.org/10.1038/s41598-017-06724-9

APA

Phan, J-A., Stokholm, K., Zareba-Paslawska, J., Jakobsen, S., Vang, K., Gjedde, A., Landau, A. M., & Romero-Ramos, M. (2017). Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease. Scientific Reports, 7, [6363]. https://doi.org/10.1038/s41598-017-06724-9

Vancouver

Phan J-A, Stokholm K, Zareba-Paslawska J, Jakobsen S, Vang K, Gjedde A o.a. Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease. Scientific Reports. 2017;7. 6363. https://doi.org/10.1038/s41598-017-06724-9

Author

Phan, Jenny-Ann ; Stokholm, Kathrine ; Zareba-Paslawska, Justyna ; Jakobsen, Steen ; Vang, Kim ; Gjedde, Albert ; Landau, Anne M. ; Romero-Ramos, Marina. / Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease. I: Scientific Reports. 2017 ; Bind 7.

Bibtex

@article{b56728d197cc40c9bf2ff79a3849d98b,
title = "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{\textquoteright}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.",
author = "Jenny-Ann Phan and Kathrine Stokholm and Justyna Zareba-Paslawska and Steen Jakobsen and Kim Vang and Albert Gjedde and Landau, {Anne M.} and Marina Romero-Ramos",
year = "2017",
doi = "10.1038/s41598-017-06724-9",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson's disease

AU - Phan, Jenny-Ann

AU - Stokholm, Kathrine

AU - Zareba-Paslawska, Justyna

AU - Jakobsen, Steen

AU - Vang, Kim

AU - Gjedde, Albert

AU - Landau, Anne M.

AU - Romero-Ramos, Marina

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-017-06724-9

DO - 10.1038/s41598-017-06724-9

M3 - Journal article

C2 - 28743955

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 6363

ER -

ID: 182485393