Neuronal cell-cycle re-entry and neurodegeneration

阿尔茨海默病（AD）和AD相关的神经退行性变的两种因果机制 肌萎缩性侧索硬化-额颞叶痴呆（ALS-FTD）等疾病是有丝分裂的重新启动， 神经元的细胞周期，以及由于核内破坏导致的核质运输受损。 核膜（NE）和核孔复合体（NPC）。深入了解这些异常是如何产生的， 方法来设计有效的治疗这些疾病;然而，很少有人知道有关启动 涉及的机制。这个应用程序将测试假设，神经元静止维持 通过抑制有丝分裂细胞周期和细胞周期重新启动的活性机制， NE/NPC解体，在有丝分裂细胞中正常发生。这一假设是基于我们对六跨膜酶GDE 2（甘油磷酸二酯磷酸二酯酶2; GDPD 5）的研究，该酶切割GPI-（糖基磷脂酰肌醇）-锚，该锚将一些蛋白质拴在质膜上。GDE 2是一种有效的 有丝分裂细胞周期的抑制剂，并诱导有丝分裂祖细胞分化为有丝分裂后的神经元， 发育中的神经系统我们发现，在缺乏GDE 2（Gde 2 KO）的成年小鼠中， 显示细胞周期再进入的证据，表明GDE 2是保持神经元处于静止状态所必需的。 引人注目的是，重新进入细胞周期的Gde 2 KO神经元显示出NE的异常组织，异常的细胞周期。 NPC蛋白质的分布和受损的核质转运，提高了细胞周期重新启动和NE/NPC分解相关联的可能性。与这一观点相一致的是，细胞周期蛋白D的遗传减少， G1/S转换的调节剂，抑制核质转运依赖性神经变性， c9 ORF 72 ALS-FTD的果蝇模型。值得注意的是，Gde 2 KO小鼠显示出年龄进行性神经变性， 并且AD患者神经元中的GDE 2分布和功能被破坏。这些观察提示 神经元静止的维持是一个主动过程，该过程的失败重新启动细胞周期，触发NE/NPC分解并诱导神经变性。目标1将确定GDE 2是否编码 维持神经元静止的新途径，并将决定神经元细胞周期重新进入信号 NE/NPC在神经元中的分解。初步RNAseq，Gde 2科斯中Wnt-报告基因小鼠的分析，以及遗传分析。 在果蝇中的研究确定了典型Wnt信号传导的异常激活作为诱导Wnt信号传导的候选途径。 神经元细胞周期再进入、NE/NPC破坏和神经变性。目标2将利用鼠标和 果蝇模型来验证这一假设。目标3中的研究将确定GDE 2功能障碍， 使用AD和ADRD的果蝇模型， 人类死后组织和iPS人类神经元。这些研究将为人类AD和ADRD中重要的神经变性的交叉疾病触发因素提供新的分子见解。

Two causal mechanisms of neurodegeneration that are found in Alzheimer's disease (AD) and AD-related diseases such as amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) are re-initiation of the mitotic cell-cycle in neurons, and impaired nucleocytoplasmic trafficking resulting from disruptions in the nuclear envelope (NE) and nuclear pore complex (NPC). Deeper insight into how these abnormalities arise would clarify approaches to design effective treatments for these diseases; however, very little is known about the initiating mechanisms involved. This application will test the hypothesis that neuronal quiescence is maintained throughout life via active mechanisms that inhibit the mitotic cell-cycle and that re-initiation of the cell-cycle leads to NE/NPC disassembly, a normal occurrence in mitotic cells. This hypothesis is based on our study of the six-transmembrane enzyme GDE2 (Glycerophosphodiester phosphodiesterase 2; GDPD5), which cleaves the GPI-(Glycosylphosphatidylinositol)-anchor that tethers some proteins to the plasma membrane. GDE2 is a potent inhibitor of the mitotic cell-cycle and induces the differentiation of mitotic progenitors into post-mitotic neurons in the developing nervous system. We discovered that in adult mice lacking GDE2 (Gde2 KO), cortical neurons show evidence of cell-cycle re-entry, suggesting that GDE2 is required to preserve neurons in a quiescent state. Strikingly, Gde2 KO neurons that have re-entered the cell-cycle show abnormal organization of the NE, aberrant distribution of NPC proteins and impaired nucleocytoplasmic transport, raising the possibility that cell-cycle re-initiation and NE/NPC breakdown are linked. Consistent with this idea, genetic reduction of cyclin D, a critical regulator of the G1/S transition, suppresses nucleocytoplasmic transport-dependent neurodegeneration in a Drosophila model of c9ORF72 ALS-FTD. Notably, Gde2 KO mice display age-progressive neurodegeneration and GDE2 distribution and function is disrupted in AD patient neurons. These observations suggest that maintenance of neuronal quiescence is an active process and that failure of this process re-initiates the cell-cycle, triggers NE/NPC breakdown and induces neurodegeneration. Aim 1 will determine if GDE2 encodes a new pathway that maintains neuronal quiescence and will determine if neuronal cell-cycle re-entry signals NE/NPC breakdown in neurons. Preliminary RNAseq, analysis of Wnt-reporter mice in Gde2 KOs, and genetic studies in Drosophila identify aberrant activation of canonical Wnt signaling as a candidate pathway that induces neuronal cell-cycle re-entry, NE/NPC breakdown and neurodegeneration. Aim 2 will utilize mouse and Drosophila models to test this hypothesis. Studies in Aim 3 will determine links between GDE2 dysfunction, neuronal cell-cycle re-entry and NE/NPC breakdown in disease using Drosophila models of AD and ADRD, human postmortem tissue and iPS human neurons. These studies will provide new molecular insight into cross-disease triggers of neurodegeneration important in human AD and ADRDs.