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α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism
BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibilit...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759291/ https://www.ncbi.nlm.nih.gov/pubmed/29310663 http://dx.doi.org/10.1186/s13024-017-0233-5 |
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author | Yun, Seung Pil Kim, Donghoon Kim, Sangjune Kim, SangMin Karuppagounder, Senthilkumar S. Kwon, Seung-Hwan Lee, Saebom Kam, Tae-In Lee, Suhyun Ham, Sangwoo Park, Jae Hong Dawson, Valina L. Dawson, Ted M. Lee, Yunjong Ko, Han Seok |
author_facet | Yun, Seung Pil Kim, Donghoon Kim, Sangjune Kim, SangMin Karuppagounder, Senthilkumar S. Kwon, Seung-Hwan Lee, Saebom Kam, Tae-In Lee, Suhyun Ham, Sangwoo Park, Jae Hong Dawson, Valina L. Dawson, Ted M. Lee, Yunjong Ko, Han Seok |
author_sort | Yun, Seung Pil |
collection | PubMed |
description | BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA(+/L444P)) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin. METHOD: We used GBA(+/L444P) mice, α-synuclein knockout (SNCA(−/−)) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA(+/L444P) mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and α-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of α-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility. RESULTS: L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA(+/L444P) mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA(+/L444P) mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA(+/L444P) mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA(+/L444P) mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA(+/L444P) mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of α-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA(+/L444P) mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA(+/L444P)α-synuclein (SNCA)(−/−) mice was nearly equal to that in SNCA(−/−) mice after MPTP treatment. CONCLUSION: Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-017-0233-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5759291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57592912018-01-10 α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism Yun, Seung Pil Kim, Donghoon Kim, Sangjune Kim, SangMin Karuppagounder, Senthilkumar S. Kwon, Seung-Hwan Lee, Saebom Kam, Tae-In Lee, Suhyun Ham, Sangwoo Park, Jae Hong Dawson, Valina L. Dawson, Ted M. Lee, Yunjong Ko, Han Seok Mol Neurodegener Research Article BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA(+/L444P)) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin. METHOD: We used GBA(+/L444P) mice, α-synuclein knockout (SNCA(−/−)) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA(+/L444P) mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and α-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of α-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility. RESULTS: L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA(+/L444P) mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA(+/L444P) mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA(+/L444P) mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA(+/L444P) mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA(+/L444P) mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of α-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA(+/L444P) mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA(+/L444P)α-synuclein (SNCA)(−/−) mice was nearly equal to that in SNCA(−/−) mice after MPTP treatment. CONCLUSION: Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-017-0233-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-01-08 /pmc/articles/PMC5759291/ /pubmed/29310663 http://dx.doi.org/10.1186/s13024-017-0233-5 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Yun, Seung Pil Kim, Donghoon Kim, Sangjune Kim, SangMin Karuppagounder, Senthilkumar S. Kwon, Seung-Hwan Lee, Saebom Kam, Tae-In Lee, Suhyun Ham, Sangwoo Park, Jae Hong Dawson, Valina L. Dawson, Ted M. Lee, Yunjong Ko, Han Seok α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism |
title | α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism |
title_full | α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism |
title_fullStr | α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism |
title_full_unstemmed | α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism |
title_short | α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism |
title_sort | α-synuclein accumulation and gba deficiency due to l444p gba mutation contributes to mptp-induced parkinsonism |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759291/ https://www.ncbi.nlm.nih.gov/pubmed/29310663 http://dx.doi.org/10.1186/s13024-017-0233-5 |
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