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A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers.
Stem Cell Reports 2017; 8(3):728-742SC

Abstract

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.

Authors+Show Affiliations

Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK.Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK. Electronic address: a.schapira@ucl.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28216145

Citation

Yang, Shi-Yu, et al. "A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers." Stem Cell Reports, vol. 8, no. 3, 2017, pp. 728-742.
Yang SY, Beavan M, Chau KY, et al. A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers. Stem Cell Reports. 2017;8(3):728-742.
Yang, S. Y., Beavan, M., Chau, K. Y., Taanman, J. W., & Schapira, A. H. V. (2017). A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers. Stem Cell Reports, 8(3), pp. 728-742. doi:10.1016/j.stemcr.2017.01.011.
Yang SY, et al. A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers. Stem Cell Reports. 2017 03 14;8(3):728-742. PubMed PMID: 28216145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers. AU - Yang,Shi-Yu, AU - Beavan,Michelle, AU - Chau,Kai-Yin, AU - Taanman,Jan-Willem, AU - Schapira,Anthony H V, Y1 - 2017/02/16/ PY - 2016/10/07/received PY - 2017/01/13/revised PY - 2017/01/16/accepted PY - 2017/2/22/pubmed PY - 2017/11/29/medline PY - 2017/2/21/entrez KW - GBA1 mutation KW - GBA1-associated PD KW - PD modeling KW - Parkinson disease KW - ambroxol KW - chaperone KW - dopaminergic neurons KW - glucocerebrosidase KW - neural crest stem cells KW - α-synuclein SP - 728 EP - 742 JF - Stem cell reports JO - Stem Cell Reports VL - 8 IS - 3 N2 - 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. SN - 2213-6711 UR - https://www.unboundmedicine.com/medline/citation/28216145/A_Human_Neural_Crest_Stem_Cell_Derived_Dopaminergic_Neuronal_Model_Recapitulates_Biochemical_Abnormalities_in_GBA1_Mutation_Carriers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-6711(17)30026-7 DB - PRIME DP - Unbound Medicine ER -