Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

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Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs. / Lillethorup, Thea Pinholt; Glud, Andreas Nørgaard; Alstrup, Aage Kristian Olsen; Mikkelsen, Trine Werenberg; Nielsen, Erik Holm Toustrup; Zaer, Hamed; Doudet, Doris J; Brooks, David J; Sørensen, Jens Christian Hedemann; Orlowski, Dariusz; Landau, Anne M.

In: Experimental Neurology, Vol. 303, 05.2018, p. 142-152.

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@article{04924050b3334730b506e52916361013,
title = "Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs",
abstract = "Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Gottingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-alpha-[C-11]dihydrotetrabenazine ([C-11]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 mu g lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36{\%} decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD.",
keywords = "Lactacystin, Microglia, Minipig, PET imaging, Parkinson's disease, Proteasome inhibition, Vesicular monoamine transporter 2, RATS, ALPHA-SYNUCLEIN, LACTACYSTIN MODEL, SUBSTANTIA-NIGRA, INCLUSION-BODIES, POSITRON-EMISSION-TOMOGRAPHY, VESICULAR MONOAMINE TRANSPORTER, IN-VIVO, NEURON DEGENERATION, PARKINSONS-DISEASE",
author = "Lillethorup, {Thea Pinholt} and Glud, {Andreas N{\o}rgaard} and Alstrup, {Aage Kristian Olsen} and Mikkelsen, {Trine Werenberg} and Nielsen, {Erik Holm Toustrup} and Hamed Zaer and Doudet, {Doris J} and Brooks, {David J} and S{\o}rensen, {Jens Christian Hedemann} and Dariusz Orlowski and Landau, {Anne M.}",
note = "Copyright {\circledC} 2018 Elsevier Inc. All rights reserved.",
year = "2018",
month = "5",
doi = "10.1016/j.expneurol.2018.02.005",
language = "English",
volume = "303",
pages = "142--152",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

AU - Lillethorup, Thea Pinholt

AU - Glud, Andreas Nørgaard

AU - Alstrup, Aage Kristian Olsen

AU - Mikkelsen, Trine Werenberg

AU - Nielsen, Erik Holm Toustrup

AU - Zaer, Hamed

AU - Doudet, Doris J

AU - Brooks, David J

AU - Sørensen, Jens Christian Hedemann

AU - Orlowski, Dariusz

AU - Landau, Anne M.

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/5

Y1 - 2018/5

N2 - Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Gottingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-alpha-[C-11]dihydrotetrabenazine ([C-11]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 mu g lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD.

AB - Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Gottingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-alpha-[C-11]dihydrotetrabenazine ([C-11]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 mu g lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD.

KW - Lactacystin

KW - Microglia

KW - Minipig

KW - PET imaging

KW - Parkinson's disease

KW - Proteasome inhibition

KW - Vesicular monoamine transporter 2

KW - RATS

KW - ALPHA-SYNUCLEIN

KW - LACTACYSTIN MODEL

KW - SUBSTANTIA-NIGRA

KW - INCLUSION-BODIES

KW - POSITRON-EMISSION-TOMOGRAPHY

KW - VESICULAR MONOAMINE TRANSPORTER

KW - IN-VIVO

KW - NEURON DEGENERATION

KW - PARKINSONS-DISEASE

U2 - 10.1016/j.expneurol.2018.02.005

DO - 10.1016/j.expneurol.2018.02.005

M3 - Journal article

C2 - 29428213

VL - 303

SP - 142

EP - 152

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

ER -