JPND: Systems Analysis of Key Nodes in Neurodegenerative Diseases

神经退行性疾病（ND）的特征在于精确神经元群体的丧失，其在分子水平上可由蛋白质稳态的改变（定义为蛋白质合成、折叠和运输的变化）触发。我们的假设是，虽然每个ND涉及不同的罪魁祸首蛋白质，并在不同的脑细胞中以不同的方式表现出来，但存在关键的共同调控节点，驱动蛋白质稳态的变化。我们的建议汇集了一个多学科的团队，在神经受体功能，细胞内蛋白质运输调节，RNA生物学，神经细胞和囊泡的分析分析，干细胞生物学和精神疾病的基因组学以及人类疾病的系统生物学分析方面的专业知识。蒙特利尔神经学研究所和医院的合作伙伴将为我们提供获得神经退行性疾病患者干细胞的独特途径。我们的目标是实现一个系统水平的了解蛋白质稳态调节在几种神经系统疾病，其中改变蛋白质稳态是牵连到了解的相似性和差异发生。具体而言，我们将：（i）从ALS/PD/AD和Batten病患者产生异源神经元群体。这将涉及所有联盟成员的生长衍生细胞;（ii）在整个疾病模型中剖析mRNA翻译的控制和重塑，以及应激颗粒在这一过程中的贡献;（iii）确定自噬、运输囊泡及其内容物如何在疾病模型中受到影响;（iv）了解不同疾病对神经元的代谢和表型影响，并在功能上验证（ii）和（iii）中鉴定的缺陷是否通过操纵信号传导途径和/或添加神经保护剂来纠正;以及（v）使用系统生物学方法来建模和绘制在疾病模型中受影响的分子途径，以定义用于治疗干预的新的调节节点和检查点。这四种疾病的全球比较将确定未来治疗干预的共同调控点，并为早期发病检测提供新的生物标志物。

Neurodegenerative diseases (ND) are characterised by the loss of precise neuronal populations, which at the molecular level can be triggered by alterations in protein homeostasis, defined as changes in protein synthesis, folding and trafficking. Our hypothesis is that although each ND involves distinct culprit proteins and manifests itself in different ways in different brain cells, there exist key common regulatory nodes driving changes in protein homeostasis. Our proposal brings together a multi-disciplinary team, bridging expertise in neuro-receptor function, intracellular protein trafficking regulation, RNA biology, analytical analysis of nerve cells and vesicles, stem cell biology and genomics of mental disorders and systems biology analysis of human diseases. Collaborative partners at Montreal Neurological Institute and Hospital will provide us unique access to neurodegenerative disease patients' stem cells. Our aim is to achieve a systems-level understanding of protein homeostasis regulation across several neurological diseases where altered protein homeostasis is implicated to understand where the similarities and differences occur. Specifically, we will: (i) generate heterologous neuronal populations from ALS/PD/AD and Batten disease patients. This will involve growing-deriving cells for all consortium members; (ii) dissect the control and remodelling of mRNA translation, and the contribution of stress granules in this process, across the disease models; (iii) establish how autophagy, trafficking vesicles and their contents are affected across the disease models; (iv) understand the metabolic and phenotypic impact of the different diseases on neurons and functionally validate if the defects identified in (ii) and (iii) are corrected by manipulating signalling pathways and/or adding neuroprotective agents; and (v) use a systems biology approach to model and map the molecular pathways affected across the disease models to define new regulatory nodes and checkpoints for therapeutic interventions. Such a global comparison of these four diseases will identify common regulatory points for future therapeutic intervention as well as provide novel biomarkers for early onset detection.