Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, PR China.
Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, PR China; Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, 100053, PR China; Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, 100053, PR China; Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, 100053, PR China; Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, PR China; National Clinical Research Center for Geriatric Disorders, Beijing, 100053, PR China.
Biochem Biophys Res Commun. 2019 Aug 13;516(1):264-269. doi: 10.1016/j.bbrc.2019.05.185. Epub 2019 Jun 21.
Clinical case study and functional characterization of the disease-associated presenilin-1 (PSEN1) mutations may help reveal the roles of PSEN1 in the pathogenesis of Alzheimer's disease (AD). By mutation screening of PSEN1, presenilin-2, and amyloid precursor protein genes in two Chinese Alzheimer's pedigrees, we identified two novel PSEN1 mutations, I249L and P433S. The two probands presented with progressive memory decline and subsequent psychiatric symptoms, with the age of onset at 54 and 34 years old, respectively. The effects of these two mutations on presenilin-1 endoproteolysis and β-amyloid (Aβ) production were examined in SH-SY5Y neuroblastoma cells infected with lentiviruses expressing presenilin-1 wild type (WT), I249L and P433S mutants. Both mutants showed increased Aβ42 levels and Aβ42/Aβ40 ratios. However, the I249L did not affect presenilin-1 endoproteolysis or Aβ43 production, whereas the P433S mutant inhibited presenilin-1 endoproteolysis and enhanced Aβ43 production. Our findings suggest that both I249L and P433S are pathogenic for early onset of AD by increasing Aβ42 production and Aβ42/Aβ40 ratios. Furthermore, P433S may contribute to the very early onset of AD by inhibiting PS1 endoproteolysis and enhancing the production of longer Aβ peptide Aβ43.
临床病例研究和疾病相关早老素-1（PSEN1）突变的功能特征分析有助于揭示 PSEN1 在阿尔茨海默病（AD）发病机制中的作用。通过对两个中国 AD 家系的 PSEN1、PSEN2 和淀粉样前体蛋白基因进行突变筛查，我们鉴定出两种新的 PSEN1 突变，即 I249L 和 P433S。这两个先证者表现为进行性记忆减退和随后的精神症状，发病年龄分别为 54 岁和 34 岁。我们在感染表达野生型 PSEN1（WT）、I249L 和 P433S 突变体的慢病毒的 SH-SY5Y 神经母细胞瘤细胞中，检测了这两种突变对早老素-1 内切酶解和 β-淀粉样蛋白（Aβ）产生的影响。两种突变体均显示 Aβ42 水平和 Aβ42/Aβ40 比值升高。然而，I249L 不影响早老素-1 内切酶解或 Aβ43 产生，而 P433S 突变抑制早老素-1 内切酶解并增强 Aβ43 产生。我们的研究结果表明，I249L 和 P433S 均可通过增加 Aβ42 产生和 Aβ42/Aβ40 比值导致 AD 的早发性发病。此外，P433S 可能通过抑制 PS1 内切酶解和增加较长 Aβ 肽 Aβ43 的产生而导致 AD 的极早发病。
