2020年1月27日，《自然—医学》在线发表了美国西达-赛奈再生医学研究所C. N. Svendsen研究小组的最新成果。他们利用年轻帕金森氏病的iPSC模型，揭示了该疾病的分子特征和新型的治疗候选物。

Title: iPSC modeling of young-onset Parkinson’s disease reveals a molecular signature of disease and novel therapeutic candidates

Author: A. H. Laperle, S. Sances, N. Yucer, V. J. Dardov, V. J. Garcia, R. Ho, A. N. Fulton, M. R. Jones, K. M. Roxas, P. Avalos, D. West, M. G. Banuelos, Z. Shu, R. Murali, N. T. Maidment, J. E. Van Eyk, M. Tagliati, C. N. Svendsen

Issue&Volume: 2020-01-27

Abstract: 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.

DOI: 10.1038/s41591-019-0739-1

Source: https://www.nature.com/articles/s41591-019-0739-1