Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2021 Jun 25;22(13):6826. doi: 10.3390/ijms22136826.
Mutations in , the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with -associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled -associated PD by crossing haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether // mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of // ( = 8), ( = 9), ( = 10) and wildtype ( = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old // mice showed more olfactory and motor deficits than wildtype mice. However, differences between // and mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.
基因突变 ，编码葡萄糖脑苷脂酶的基因，是帕金森病（PD）的常见遗传风险因素。虽然这种关系的机制尚不清楚，但与 -相关的 PD 患者的发病通常比特发性 PD 更早且进展更快。以前，我们通过将半合子不足的小鼠与过度表达人类突变α-突触核蛋白转基因（）的小鼠杂交来模拟 -相关的 PD，观察到更早的死亡、更短的寿命和更快的症状进展，尽管未进行行为测试。为了评估 // 小鼠是否表现出前驱性行为表型，我们研究了三种主要的 PD 特征：嗅觉辨别、记忆功能障碍和运动功能。通过埋藏颗粒测试、新物体识别测试和梁行走，在 8 至 23 个月龄之间评估了 // （ = 8）、（ = 9）、（ = 10）和野生型（ = 6）小鼠的纵向表现。15 个月大的 // 小鼠比野生型小鼠表现出更多的嗅觉和运动缺陷。然而，// 和 小鼠之间的差异通常没有达到统计学意义，可能是由于样本量较小。此外，尽管 // 半合子不足导致更快的死亡，但这可能不会导致更早的前驱期，其他因素，包括衰老、氧化应激和表观遗传学，可能会导致更严重的疾病进程。
