γ-secretase promotes postsynaptic maturation through the cleavage of a Wnt receptor

An emerging feature of neurodegenerative disease is synaptic dysfunction and loss, leading to the suggestion that mechanisms required for synaptic maturation may be linked to disease. Synaptic maturation requires the transmission of signals between nascent synaptic sites and the nucleus, but how these signals are generated is not well understood. We posit that proteolytic cleavage of receptors, which enables their translocation to the nucleus, may be a shared molecular mechanism between the events that promote synaptic maturation and those linked to later-onset disorders of the nervous system, including neurodegenerative disease. Here we show during synaptic development, that cleavage of synaptic maturation molecules requires γ-secretase, a protein complex linked to Alzheimer’s Disease, a devastating neurodegenerative condition, is required for postsynaptic maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to appropriately recruit postsynaptic scaffolding and cytoskeletal proteins, and mutant larvae display behavioral deficits. At the NMJ, γ-secretase promotes synaptic maturation through the cleavage of the Wnt receptor Fz2, and the subsequent entry of its C-terminus into the nucleus. A developmental synaptic role for γ-secretase is also conserved in both the Drosophila central nervous system and mammalian cortical neuron dendrites. Finally, we found that similar maturation defects are evident in fly models for ALS, Alzheimer’s, Huntington’s, and Parkinson’s Diseases. The previously unknown, but conserved, role for γ-secretase coupled with its well-known role in neurodegenerative disease suggest that neurodevelopmental defects may be common to diverse neurodegenerative disease models.

神经退行性疾病的一个新兴特征是突触功能障碍和丧失，这导致人们提出突触成熟所需的机制可能与疾病有关。突触成熟需要在新生突触位点和细胞核之间传递信号，但这些信号是如何产生的还不太清楚。我们假定受体的蛋白水解切割（这种切割使其能够易位到细胞核）可能是促进突触成熟的事件与那些与神经系统后期发病的疾病（包括神经退行性疾病）相关的事件之间的一种共同分子机制。在这里，我们在突触发育过程中表明，突触成熟分子的切割需要γ-分泌酶，这是一种与阿尔茨海默病（一种毁灭性的神经退行性疾病）相关的蛋白质复合物，它是突触后成熟所必需的。在没有γ-分泌酶的情况下，果蝇的神经肌肉突触无法适当地募集突触后支架和细胞骨架蛋白，并且突变幼虫表现出行为缺陷。在神经肌肉接头处，γ-分泌酶通过切割Wnt受体Fz2以及其C末端随后进入细胞核来促进突触成熟。γ-分泌酶在发育中的突触作用在果蝇中枢神经系统和哺乳动物皮质神经元树突中也是保守的。最后，我们发现类似的成熟缺陷在肌萎缩侧索硬化症、阿尔茨海默病、亨廷顿病和帕金森病的果蝇模型中也很明显。γ-分泌酶以前未知但保守的作用，以及它在神经退行性疾病中众所周知的作用表明，神经发育缺陷可能在多种神经退行性疾病模型中是常见的。