诱导多能干细胞
帕金森病
生物
疾病
α-突触核蛋白
医学
细胞生物学
多巴胺能
多巴胺
基因
遗传学
内科学
内分泌学
胚胎干细胞
作者
Alex Laperle,Samuel Sances,Nur Yucer,Victoria Dardov,Veronica J. Garcia,Ritchie Ho,AnneB Fulton,Michelle R. Jones,Kristina Roxas,Pablo Avalos,Destiny West,Maria G. Bañuelos,Shuie Zhan,Ramachandran Murali,Nigel T. Maidment,Jennifer E. Van Eyk,Michele Tagliati,Clive N. Svendsen
出处
期刊:Nature Medicine
[Springer Nature]
日期:2020-01-27
卷期号:26 (2): 289-299
被引量:102
标识
DOI:10.1038/s41591-019-0739-1
摘要
Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.
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