Ganguly Atish, Feldman R M Renny, Guo Ming
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Hum Mol Genet. 2008 Jan 15;17(2):293-302. doi: 10.1093/hmg/ddm305. Epub 2007 Oct 18.
The majority of familial Alzheimer's disease (AD) cases are caused by mutations in presenilins, therefore, identifying regulators of presenilins is crucial for understanding AD pathogenesis. Ubiquilin 1 (UBQLN1) binds Presenilins in mammalian cells; however, the functional significance of this interaction in vivo remains unclear. Moreover, while genetic variants in UBQLN1 have recently been reported to associate with an increased risk for AD, whether these variants have altered function is unknown. Here, we show that Drosophila Ubiquilin (Ubqn) binds to Drosophila Presenilin (Psn), and that loss of ubqn function suppresses phenotypes that arise from loss of psn function in vivo. In addition, overexpression of ubqn in the eye results in adult-onset, age-dependent retinal degeneration, which is at least partially apoptotic in nature. The degeneration associated with ubqn overexpression can also be suppressed by psn overexpression and enhanced by expression of a dominant negative version of Psn. Remarkably, expression of the human AD-associated variant of UBQLN1 leads to more severe degeneration than does comparable expression of the human wildtype UBQLN1. Together, these data identify Ubqn as a regulator of Psn, support an important role for UBQLN1 in AD pathogenesis, and suggest the possibility that expression of a human AD-associated variant can cause neurodegeneration independent of amyloid production.
大多数家族性阿尔茨海默病（AD）病例是由早老素突变引起的，因此，确定早老素的调节因子对于理解AD发病机制至关重要。泛素连接酶1（UBQLN1）在哺乳动物细胞中与早老素结合；然而，这种相互作用在体内的功能意义仍不清楚。此外，虽然最近报道UBQLN1中的基因变异与AD风险增加有关，但这些变异是否改变了功能尚不清楚。在这里，我们表明果蝇泛素连接酶（Ubqn）与果蝇早老素（Psn）结合，并且Ubqn功能丧失会抑制体内Psn功能丧失所产生的表型。此外，在眼睛中过表达Ubqn会导致成年期、年龄依赖性视网膜变性，其本质上至少部分是凋亡性的。与Ubqn过表达相关的变性也可以通过Psn过表达来抑制，并通过显性负性版本的Psn表达来增强。值得注意的是，与人类野生型UBQLN1的可比表达相比，人类AD相关变异体UBQLN1的表达导致更严重的变性。总之，这些数据确定Ubqn为Psn的调节因子，支持UBQLN1在AD发病机制中的重要作用，并表明人类AD相关变异体的表达可能导致独立于淀粉样蛋白产生的神经变性。
