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.

年轻发病帕金森病 (YOPD) 的定义是发病时间<50 岁，约占所有帕金森病病例的 10%，虽然有些病例与已知的基因突变有关，但大多数病例并非如此。这里，诱导多能干细胞是从对照个体和没有已知突变的 YOPD 患者中产生的。在分化为含有多巴胺神经元的培养物后，来自 YOPD 患者的诱导多能干细胞表现出可溶性 α-突触核蛋白和磷酸化蛋白激酶 Cα 的积累增加，以及溶酶体膜蛋白（如 LAMP1）的丰度减少。测试溶酶体功能激活剂表明，特定的佛波酯（例如 PEP005）可降低 α-突触核蛋白和磷酸化蛋白激酶 Cα 水平，同时增加 LAMP1 丰度。有趣的是，α-突触核蛋白的减少是通过蛋白酶体降解发生的。PEP005 递送至小鼠纹状体也减少了体内 α-突触核蛋白的产生。诱导多能干细胞衍生的多巴胺能培养物揭示了 YOPD 患者的特征，这些患者没有已知的帕金森病相关突变，这表明可能还有其他遗传因素导致了这种疾病。这种特征被特定的佛波酯标准化，使它们成为有前途的治疗候选者。