Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
J Alzheimers Dis. 2011;23(4):701-7. doi: 10.3233/JAD-2010-101416.
BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor that interacts with tau and regulates its proteasomal degradation. A significant increase of the BAG-1M isoform was found in Alzheimer's disease (AD) brains, and the protein co-localized with tau and amyloid. We carried out an association study of BAG1 in a population of 291 patients clinically diagnosed with frontotemporal lobar degeneration (FTLD), none of whom was a carrier of mutations in progranulin or microtubule associated protein tau genes and 374 with AD as compared with 314 age- and gender-matched controls. In addition, another candidate named Chromatin-modifying protein 5 (CHMP5) and located in the same linkage disequilibrium block, has been included in this study. The distribution of the two single nucleotide polymorphism (SNPs), rs844239 in CHMP5 and rs706118 in BAG1, covering 100% gene variability, were determined. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD as compared with controls (16.7 versus 23.9%; p = 0.007, OR: 0.35, CI: 0.25-0.50), whereas allelic frequency of the SNP in patients with AD was similar to controls (24.3%, p > 0.05). Conversely, no significant association was found as regards CHMP5 rs844239. Stratifying according to gender, no differences were observed. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD, suggesting its specific role in a pathogenic event in FTLD. Nevertheless, a replication study would be needed to confirm these preliminary results.
B 细胞淋巴瘤-2 相关抗凋亡基因 1（BAG1）是一种抗凋亡因子，与 tau 相互作用并调节其蛋白酶体降解。在阿尔茨海默病（AD）脑中发现 BAG-1M 同工型显著增加，该蛋白与 tau 和淀粉样蛋白共定位。我们在 291 名临床诊断为额颞叶变性（FTLD）的患者人群中进行了 BAG1 的关联研究，这些患者均未携带颗粒蛋白或微管相关蛋白 tau 基因突变，而 374 名患者患有 AD，与 314 名年龄和性别匹配的对照组进行比较。此外，本研究还纳入了另一个名为染色质修饰蛋白 5（CHMP5）的候选基因，该基因位于同一连锁不平衡块中。确定了 CHMP5 中的两个单核苷酸多态性（SNP）rs844239 和 BAG1 中的 rs706118 的分布，涵盖了 100%的基因变异性。与对照组相比，FTLD 患者的 BAG-1 rs706118 SNP 的等位基因频率显著降低（16.7%比 23.9%；p=0.007，OR：0.35，CI：0.25-0.50），而 AD 患者的 SNP 等位基因频率与对照组相似（24.3%，p>0.05）。相反，CHMP5 rs844239 没有发现显著的关联。根据性别分层，没有观察到差异。BAG-1 rs706118 SNP 可能作为散发性 FTLD 的保护因子，但不是 AD 的保护因子，提示其在 FTLD 中的特定致病事件中起作用。然而，需要进行复制研究来证实这些初步结果。
