JPND: Systems Analysis of Key Nodes in Neurodegenerative Diseases

神经退行性疾病（ND）的特征是精确神经元群的丧失，在分子水平上，可由蛋白质稳态的改变触发，定义为蛋白质合成、折叠和运输的变化。我们的假设是，尽管每种ND涉及不同的罪魁祸首蛋白，并且在不同的脑细胞中以不同的方式表现出来，但存在驱动蛋白质稳态变化的关键共同调节节点。我们的提案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，神经细胞和囊泡分析分析，干细胞生物学和精神障碍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。蒙特利尔神经研究所和医院的合作伙伴将为我们提供获取神经退行性疾病患者干细胞的独特途径。我们的目标是实现对几种神经系统疾病中蛋白质稳态调节的系统级理解，其中涉及蛋白质稳态改变，以了解相似和差异发生的地方。具体来说，我们将：(i)从ALS/PD/AD和Batten病患者中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；（三）确定自噬、贩运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，并从功能上验证（ii）和（iii）中发现的缺陷是否可以通过操纵信号通路和/或添加神经保护剂来纠正；(v)使用系统生物学方法来建模和绘制受疾病模型影响的分子途径，以定义治疗干预的新调控节点和检查点。这种对这四种疾病的全球比较将为未来的治疗干预确定共同的调控点，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.