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Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein

Parkinson’s disease (PD) and related disorders are characterized by filamentous or fibrous structures consisting of abnormal α-synuclein in the brains of patients, and the distributions and spread of these pathologies are closely correlated with disease progression. L-DOPA (a dopamine precursor) is...

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Autores principales: Shimozawa, Aki, Fujita, Yuuki, Kondo, Hiromi, Takimoto, Yu, Terada, Makoto, Sanagi, Masanao, Hisanaga, Shin-ichi, Hasegawa, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587610/
https://www.ncbi.nlm.nih.gov/pubmed/31258461
http://dx.doi.org/10.3389/fnins.2019.00595
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author Shimozawa, Aki
Fujita, Yuuki
Kondo, Hiromi
Takimoto, Yu
Terada, Makoto
Sanagi, Masanao
Hisanaga, Shin-ichi
Hasegawa, Masato
author_facet Shimozawa, Aki
Fujita, Yuuki
Kondo, Hiromi
Takimoto, Yu
Terada, Makoto
Sanagi, Masanao
Hisanaga, Shin-ichi
Hasegawa, Masato
author_sort Shimozawa, Aki
collection PubMed
description Parkinson’s disease (PD) and related disorders are characterized by filamentous or fibrous structures consisting of abnormal α-synuclein in the brains of patients, and the distributions and spread of these pathologies are closely correlated with disease progression. L-DOPA (a dopamine precursor) is the most effective therapy for PD, but it remains unclear whether the drug has any effect on the formation and propagation of pathogenic abnormal α-synuclein in vivo. Here, we tested whether or not L-DOPA influences the prion-like spread of α-synuclein pathologies in a wild-type (WT) mouse model of α-synuclein propagation. To quantitative the pathological α-synuclein in mice, we prepared brain sections stained with an anti-phosphoSer129 (PS129) antibody after pretreatments with autoclaving and formic acid, and carefully analyzed positive aggregates on multiple sections covering the areas of interest using a microscope. Notably, a significant reduction in the accumulation of phosphorylated α-synuclein was detected in substantia nigra of L-DOPA/benserazide (a dopamine decarboxylase inhibitor)-treated mice, compared with control mice. These results suggest that L-DOPA may slow the progression of PD in vivo by suppressing the aggregation of α-synuclein in dopaminergic neurons and the cell-to-cell propagation of abnormal α-synuclein. This is the first report describing the suppressing effect of L-DOPA/benserazide on the propagation of pathological α-synuclein. The experimental protocols and detection methods in this study are expected to be useful for evaluation of drug candidates or new therapies targeting the propagation of α-synuclein.
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spelling pubmed-65876102019-06-28 Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein Shimozawa, Aki Fujita, Yuuki Kondo, Hiromi Takimoto, Yu Terada, Makoto Sanagi, Masanao Hisanaga, Shin-ichi Hasegawa, Masato Front Neurosci Neuroscience Parkinson’s disease (PD) and related disorders are characterized by filamentous or fibrous structures consisting of abnormal α-synuclein in the brains of patients, and the distributions and spread of these pathologies are closely correlated with disease progression. L-DOPA (a dopamine precursor) is the most effective therapy for PD, but it remains unclear whether the drug has any effect on the formation and propagation of pathogenic abnormal α-synuclein in vivo. Here, we tested whether or not L-DOPA influences the prion-like spread of α-synuclein pathologies in a wild-type (WT) mouse model of α-synuclein propagation. To quantitative the pathological α-synuclein in mice, we prepared brain sections stained with an anti-phosphoSer129 (PS129) antibody after pretreatments with autoclaving and formic acid, and carefully analyzed positive aggregates on multiple sections covering the areas of interest using a microscope. Notably, a significant reduction in the accumulation of phosphorylated α-synuclein was detected in substantia nigra of L-DOPA/benserazide (a dopamine decarboxylase inhibitor)-treated mice, compared with control mice. These results suggest that L-DOPA may slow the progression of PD in vivo by suppressing the aggregation of α-synuclein in dopaminergic neurons and the cell-to-cell propagation of abnormal α-synuclein. This is the first report describing the suppressing effect of L-DOPA/benserazide on the propagation of pathological α-synuclein. The experimental protocols and detection methods in this study are expected to be useful for evaluation of drug candidates or new therapies targeting the propagation of α-synuclein. Frontiers Media S.A. 2019-06-14 /pmc/articles/PMC6587610/ /pubmed/31258461 http://dx.doi.org/10.3389/fnins.2019.00595 Text en Copyright © 2019 Shimozawa, Fujita, Kondo, Takimoto, Terada, Sanagi, Hisanaga and Hasegawa. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Shimozawa, Aki
Fujita, Yuuki
Kondo, Hiromi
Takimoto, Yu
Terada, Makoto
Sanagi, Masanao
Hisanaga, Shin-ichi
Hasegawa, Masato
Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
title Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
title_full Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
title_fullStr Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
title_full_unstemmed Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
title_short Effect of L-DOPA/Benserazide on Propagation of Pathological α-Synuclein
title_sort effect of l-dopa/benserazide on propagation of pathological α-synuclein
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587610/
https://www.ncbi.nlm.nih.gov/pubmed/31258461
http://dx.doi.org/10.3389/fnins.2019.00595
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