α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism
Abstract 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 susce...
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2018-01-01
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Series: | Molecular Neurodegeneration |
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Online Access: | http://link.springer.com/article/10.1186/s13024-017-0233-5 |
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doaj-213271272ea14b04817b478ead2a71ae |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Seung Pil Yun Donghoon Kim Sangjune Kim SangMin Kim Senthilkumar S. Karuppagounder Seung-Hwan Kwon Saebom Lee Tae-In Kam Suhyun Lee Sangwoo Ham Jae Hong Park Valina L. Dawson Ted M. Dawson Yunjong Lee Han Seok Ko |
spellingShingle |
Seung Pil Yun Donghoon Kim Sangjune Kim SangMin Kim Senthilkumar S. Karuppagounder Seung-Hwan Kwon Saebom Lee Tae-In Kam Suhyun Lee Sangwoo Ham Jae Hong Park Valina L. Dawson Ted M. Dawson Yunjong Lee Han Seok Ko α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism Molecular Neurodegeneration Parkinson’s disease GBA MPTP Mitochondrial dysfunction α-synuclein |
author_facet |
Seung Pil Yun Donghoon Kim Sangjune Kim SangMin Kim Senthilkumar S. Karuppagounder Seung-Hwan Kwon Saebom Lee Tae-In Kam Suhyun Lee Sangwoo Ham Jae Hong Park Valina L. Dawson Ted M. Dawson Yunjong Lee Han Seok Ko |
author_sort |
Seung Pil Yun |
title |
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_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_sort |
α-synuclein accumulation and gba deficiency due to l444p gba mutation contributes to mptp-induced parkinsonism |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2018-01-01 |
description |
Abstract 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. |
topic |
Parkinson’s disease GBA MPTP Mitochondrial dysfunction α-synuclein |
url |
http://link.springer.com/article/10.1186/s13024-017-0233-5 |
work_keys_str_mv |
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doaj-213271272ea14b04817b478ead2a71ae2020-11-24T21:50:10ZengBMCMolecular Neurodegeneration1750-13262018-01-0113111910.1186/s13024-017-0233-5α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonismSeung Pil Yun0Donghoon Kim1Sangjune Kim2SangMin Kim3Senthilkumar S. Karuppagounder4Seung-Hwan Kwon5Saebom Lee6Tae-In Kam7Suhyun Lee8Sangwoo Ham9Jae Hong Park10Valina L. Dawson11Ted M. Dawson12Yunjong Lee13Han Seok Ko14Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineDivision of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research InstituteNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineDivision of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research InstituteNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of MedicineAbstract 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.http://link.springer.com/article/10.1186/s13024-017-0233-5Parkinson’s diseaseGBAMPTPMitochondrial dysfunctionα-synuclein |