Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
Neurobiol Aging. 2018 May;65:192-200. doi: 10.1016/j.neurobiolaging.2018.01.004. Epub 2018 Jan 31.
TgMHu2ME199K mice, a transgenic line mimicking genetic prion disease, are born healthy and gradually deteriorate to a terminal neurological condition concomitant with the accumulation of disease-related PrP. To investigate whether transplantation of neural progenitor cells (NPCs) to these mice can delay disease aggravation, we first tested the properties of mutant PrP in homogenates and enriched NPCs from TgMHu2ME199K embryos, as compared to PrP in sick TgMHu2ME199K brains. Next, we tested the clinical effect of NPCs transplantation into newborn TgMHu2ME199K mice. We show that mutant PrP does not convert into a disease-related isoform while in progenitor cells. Most important, transplantation of both wild type and transgenic NPCs significantly delayed the progression of spontaneous prion disease in TgMHu2ME199K mice. While the strong clinical effect was not accompanied by a reduced accumulation of disease-related PrP, treated mouse brains presented a significant reduction in amyloid glycosaminoglycans and preservation of neurogenesis levels, indicating a strong neuroprotective effect. These results may encourage the investigation of new pathways for treatment in these terrible diseases.
TgMHu2ME199K 小鼠是一种模拟遗传朊病毒病的转基因系，出生时健康，但随着疾病相关 PrP 的积累，逐渐恶化至终末期神经状态。为了研究向这些小鼠移植神经祖细胞 (NPC) 是否可以延缓疾病恶化，我们首先测试了 TgMHu2ME199K 胚胎匀浆和富集 NPC 中突变型 PrP 的特性，并与患病 TgMHu2ME199K 大脑中的 PrP 进行了比较。接下来，我们测试了 NPC 移植到新生 TgMHu2ME199K 小鼠中的临床效果。我们发现，突变型 PrP 在祖细胞中不会转化为疾病相关的异构体。最重要的是，向 TgMHu2ME199K 小鼠中移植野生型和转基因 NPC 均可显著延缓自发性朊病毒病的进展。虽然强烈的临床效果并没有伴随着疾病相关 PrP 积累的减少，但治疗后的小鼠大脑中淀粉样糖胺聚糖显著减少，神经发生水平保持不变，表明具有强烈的神经保护作用。这些结果可能鼓励对这些可怕疾病的新治疗途径进行研究。
