Neuronal cell-cycle re-entry and neurodegeneration

神经元细胞周期重入和神经变性

基本信息

批准号：
10027420
负责人：
Thomas E. Lloyd
金额：
$ 66.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10027420
关键词：
Adult Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Animals Antimitotic Agents Automobile Driving Autopsy Biological Assay Biological Models C9ORF72 Cell Cycle Cell Cycle Inhibition Cell membrane Cells Cleaved cell Cyclin D1 Development Disease Drosophila cyclin D Drosophila genus Embryonic Development Enzymes Event Excision Exhibits Failure Functional disorder G1 Phase G1/S Transition GPI Membrane Anchors Genes Genetic Genetic Suppression Genetic study Glycosylphosphatidylinositols Human Huntington Disease Impairment Knockout Mice Lamin Type A Life Link Maintenance Mediating Mitosis Mitotic Mitotic Cell Cycle Modeling Molecular Mus Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Nuclear Envelope Nuclear Pore Complex Nuclear Pore Complex Proteins Outcome Pathogenesis Pathology Pathway interactions Patients Physiological Process Proteins Regulatory Pathway Reporter Signal Transduction Spatial Distribution Specificity System Testing Therapeutic Intervention Tissues WNT Signaling Pathway Work base cellular pathology design effective therapy fly frontotemporal lobar dementia-amyotrophic lateral sclerosis glycerophosphodiester phosphodiesterase human disease induced pluripotent stem cell insight neuron loss neuronal survival new therapeutic target novel nucleocytoplasmic transport preservation prevent progenitor progressive neurodegeneration protein transport stem cells trafficking transcriptome sequencing

项目摘要

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.

在阿尔茨海默氏病（AD）和AD相关的两种神经变性的因果机制肌萎缩性侧索硬化症等疾病 - 氟次痴呆（ALS-FTD）是有丝分裂的神经元中的细胞周期，以及因核中断而导致的核细胞流量受损包膜（NE）和核孔复合物（NPC）。更深入了解这些异常将如何澄清为这些疾病设计有效治疗方法的方法；但是，关于启动知之甚少涉及的机制。该应用将测试保持神经元静止的假设在整个生命中，都通过抑制有丝分裂细胞周期和细胞周期铅的重新生成的主动机制 NE/NPC分解，有丝分裂细胞正常发生。该假设基于我们对六跨膜酶GDE2（甘油磷酸磷酸酯磷酸二酯酶2; gdpd5）的研究，该酶将GPI（糖基磷脂酰辛糖醇）裂解，从而将某些蛋白质转化为铂骨膜骨架。 GDE2是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神经元发育中的神经系统。我们发现在缺乏GDE2（GDE2 KO）的成年小鼠中，皮质神经元显示了细胞周期重新进入的证据，这表明GDE2需要保持静止状态的神经元。引人注目的是，重新进入细胞周期显示NE，异常组织的GDE2 KO神经元异常 NPC蛋白的分布和受损的核细胞质转运，从而增加了细胞周期重新定位和NE/NPC分解的可能性。与这个想法一致，细胞周期蛋白D的遗传减少，一个关键 G1/s转变的调节剂，抑制A中的核细胞依赖性神经变性 C9orf72 ALS-FTD的果蝇模型。值得注意的是，GDE2 KO小鼠展示了增长的神经变性 AD患者神经元中的GDE2分布和功能被破坏。这些观察表明神经元静止的维持是一个主动过程，该过程的失败会重新启动细胞周期，触发NE/NPC分解并诱导神经变性。 AIM 1将确定GDE2是否编码保持神经元静止的新途径，并将确定神经元细胞周期是否重新输入信号神经元中的NE/NPC分解。初步RNASEQ，GDE2 KOS中Wnt-Reporter小鼠的分析和遗传果蝇的研究确定了典型的Wnt信号的异常激活是诱导的候选途径神经元细胞周期重新进入，NE/NPC分解和神经变性。 AIM 2将利用鼠标，果蝇模型以检验该假设。 AIM 3中的研究将确定GDE2功能障碍之间的联系，使用AD和ADRD的果蝇模型，神经元细胞周期的疾病中的NE/NPC分解，人验尸组织和IPS人类神经元。这些研究将为对人AD和ADRD重要的神经变性触发的跨疾病触发器提供新的分子见解。