A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers
Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuc...
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doaj-0ad61c3a257e44269be48593e4f9ee2b2020-11-24T23:59:39ZengElsevierStem Cell Reports2213-67112017-03-018372874210.1016/j.stemcr.2017.01.011A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation CarriersShi-Yu Yang0Michelle Beavan1Kai-Yin Chau2Jan-Willem Taanman3Anthony H.V. Schapira4Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UKDepartment of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UKDepartment of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UKDepartment of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UKDepartment of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UKNumerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.http://www.sciencedirect.com/science/article/pii/S2213671117300267neural crest stem cellsParkinson diseaseglucocerebrosidaseα-synucleinchaperonePD modelingdopaminergic neuronsGBA1 mutationambroxolGBA1-associated PD |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shi-Yu Yang Michelle Beavan Kai-Yin Chau Jan-Willem Taanman Anthony H.V. Schapira |
spellingShingle |
Shi-Yu Yang Michelle Beavan Kai-Yin Chau Jan-Willem Taanman Anthony H.V. Schapira A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers Stem Cell Reports neural crest stem cells Parkinson disease glucocerebrosidase α-synuclein chaperone PD modeling dopaminergic neurons GBA1 mutation ambroxol GBA1-associated PD |
author_facet |
Shi-Yu Yang Michelle Beavan Kai-Yin Chau Jan-Willem Taanman Anthony H.V. Schapira |
author_sort |
Shi-Yu Yang |
title |
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers |
title_short |
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers |
title_full |
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers |
title_fullStr |
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers |
title_full_unstemmed |
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers |
title_sort |
human neural crest stem cell-derived dopaminergic neuronal model recapitulates biochemical abnormalities in gba1 mutation carriers |
publisher |
Elsevier |
series |
Stem Cell Reports |
issn |
2213-6711 |
publishDate |
2017-03-01 |
description |
Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD. |
topic |
neural crest stem cells Parkinson disease glucocerebrosidase α-synuclein chaperone PD modeling dopaminergic neurons GBA1 mutation ambroxol GBA1-associated PD |
url |
http://www.sciencedirect.com/science/article/pii/S2213671117300267 |
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