α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease

Kathrine Stokholm; Majken Borup Thomsen; Jenny Ann Phan; Line K. Møller; Cecilie Bay-Richter; Søren H. Christiansen; David P.D. Woldbye; Marina Romero-Ramos; Anne M. Landau

doi:10.3390/biomedicines9121876

α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease

Kathrine Stokholm, Majken Borup Thomsen, Jenny Ann Phan, Line K. Møller, Cecilie Bay-Richter, Søren H. Christiansen, David P.D. Woldbye, Marina Romero-Ramos, Anne M. Landau^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

8 Citations (Scopus)

Abstract

Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson’s disease (PD). We previously reported that unilateral intrani-gral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [³ H]raclopride, [³ H]DTBZ, [³ H]GBR12935, [³ H]PK11195, and [³ H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mito-chondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.

Original language	English
Article number	1876
Journal	Biomedicines
Volume	9
Issue	12
ISSN	2227-9059
DOIs	https://doi.org/10.3390/biomedicines9121876
Publication status	Published - Dec 2021

Keywords

Adeno-associated viral vectors
Autoradiography
Dopamine
Neuroinflam-mation
Parkinson’s disease
Synaptic vesicle glycoprotein 2A
α-synuclein

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Stokholm, K., Thomsen, M. B., Phan, J. A., Møller, L. K., Bay-Richter, C., Christiansen, S. H., Woldbye, D. P. D., Romero-Ramos, M., & Landau, A. M. (2021). α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease. Biomedicines, 9(12), Article 1876. https://doi.org/10.3390/biomedicines9121876

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title = "α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson{\textquoteright}s Disease",

abstract = "Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson{\textquoteright}s disease (PD). We previously reported that unilateral intrani-gral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [3 H]raclopride, [3 H]DTBZ, [3 H]GBR12935, [3 H]PK11195, and [3 H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mito-chondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.",

keywords = "Adeno-associated viral vectors, Autoradiography, Dopamine, Neuroinflam-mation, Parkinson{\textquoteright}s disease, Synaptic vesicle glycoprotein 2A, α-synuclein",

author = "Kathrine Stokholm and Thomsen, {Majken Borup} and Phan, {Jenny Ann} and M{\o}ller, {Line K.} and Cecilie Bay-Richter and Christiansen, {S{\o}ren H.} and Woldbye, {David P.D.} and Marina Romero-Ramos and Landau, {Anne M.}",

year = "2021",

month = dec,

doi = "10.3390/biomedicines9121876",

language = "English",

volume = "9",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI",

number = "12",

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α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease. / Stokholm, Kathrine; Thomsen, Majken Borup; Phan, Jenny Ann et al.
In: Biomedicines, Vol. 9, No. 12, 1876, 12.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease

AU - Stokholm, Kathrine

AU - Thomsen, Majken Borup

AU - Phan, Jenny Ann

AU - Møller, Line K.

AU - Bay-Richter, Cecilie

AU - Christiansen, Søren H.

AU - Woldbye, David P.D.

AU - Romero-Ramos, Marina

AU - Landau, Anne M.

PY - 2021/12

Y1 - 2021/12

N2 - Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson’s disease (PD). We previously reported that unilateral intrani-gral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [3 H]raclopride, [3 H]DTBZ, [3 H]GBR12935, [3 H]PK11195, and [3 H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mito-chondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.

AB - Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson’s disease (PD). We previously reported that unilateral intrani-gral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [3 H]raclopride, [3 H]DTBZ, [3 H]GBR12935, [3 H]PK11195, and [3 H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mito-chondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.

KW - Adeno-associated viral vectors

KW - Autoradiography

KW - Dopamine

KW - Neuroinflam-mation

KW - Parkinson’s disease

KW - Synaptic vesicle glycoprotein 2A

KW - α-synuclein

U2 - 10.3390/biomedicines9121876

DO - 10.3390/biomedicines9121876

M3 - Journal article

C2 - 34944691

AN - SCOPUS:85121740483

SN - 2227-9059

VL - 9

JO - Biomedicines

JF - Biomedicines

IS - 12

M1 - 1876

ER -

α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson’s Disease

Abstract

Keywords

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