Determining neuroprotective autophagy functions using different types of human neurons

我们的主要目标是利用人类神经元解剖控制神经活动和疾病相关蛋白（如APP/代谢物、tau、-synuclein和TDP43）清除的保护性自噬的分子机制，并确定选择性神经元的易感性是否可能由自噬缺陷引起，而自噬缺陷与神经退行性疾病（如阿尔茨海默病（AD））和其他类型的痴呆症（包括路易体痴呆（DLB））有关。帕金森病痴呆（PDD）和额颞叶痴呆（FTD）。上述疾病的病理特征是疾病蛋白通过突触间细胞传递积累和扩散。例如，-突触核蛋白病理从脑干向边缘和新皮质结构的扩散与PDD中出现的痴呆有关。由于DLB、PDD、AD和FTD之间含有tau、-synuclein和TDP43的病理有明显的重叠，了解上述疾病蛋白聚集和扩散的共同致病机制对于开发有效的DLB、PDD、AD和FTD的疾病改善治疗至关重要。然而，尽管自噬研究取得了进展，但对神经元自噬特别是人类神经元自噬的认识不足，阻碍了我们对疾病机制的认识和特异性自噬药物的开发。越来越多的证据表明，自噬在降解特定蛋白质和细胞器方面具有选择性，这是由各种自噬受体/接头介导的。新出现的证据表明自噬和突触运输途径之间存在交叉对话。识别神经元中特定的自噬货物有望提供对神经活动的自噬调节机制的深入了解，从而提供神经保护。在这个应用中，我们将通过使用不同类型的诱导人类神经元来确定神经元保护性自噬。我们将确定在不同类型的人类神经元中调控APP/代谢物、tau、-synuclein和TDP43稳态的选择性自噬的分子决定因素。我们将利用人诱导神经元确定自噬控制神经元功能的分子机制（目的1），并利用人in细胞确定自噬在控制-synuclein、tau、APP/代谢物和TDP-43蛋白稳态中的神经保护功能（目的2）。我们的研究有望阐明人类神经元的自噬功能，并揭示主要神经退行性疾病伴痴呆的选择性神经元易损性背后的疾病蛋白积累和扩散机制。

Our primary goal is to use human neurons to dissect molecular mechanism for protective autophagy that controls neural activities and clearance of disease related proteins such as APP/metabolites, tau, -synuclein, and TDP43, and to determine whether the vulnerability of selective neurons can be caused by autophagy deficiency, which are associated with neurodegenerative diseases such as Alzheimer’s disease (AD) and other types of dementia including dementia with Lewy body (DLB), Parkinson’s disease dementia (PDD) and frontotemporal dementia (FTD). A pathological hallmark of the above diseases is the accumulation and spreading of disease proteins through trans-synaptic cell-to-cell transmission. For example, the spread of -synuclein pathologies from the brainstem to limbic and neocortical structures are correlated with emerging dementia in PDD. Due to the significant overlap of pathologies containing tau, -synuclein, and TDP43 between DLB, PDD, AD and FTD, understanding of common pathogenic mechanisms underlying the above disease protein aggregates and spreading is crucial for the development of effective disease-modifying treatments for DLB, PDD, AD and FTD. However, despite the advance in autophagy study, the lack of knowledge in neuronal autophagy particularly in human neurons impedes our understanding of disease mechanism and development of specific autophagy drugs. Increasing evidence has demonstrated the selectivity of autophagy in degrading specific proteins and organelles, which are mediated by various autophagy receptors/adaptors. Emerging evidence suggests the cross-talk between autophagy and synaptic trafficking pathways. Identification of specific autophagy cargoes in neurons is expected to provide an insight into the mechanism for autophagic regulation of neural activities, thus offering neuroprotection. In this application we will determine neuronprotective autophagy by using different types of induced human neurons. We will identify the molecular determinants of selective autophagy that regulates the homeostasis of APP/metabolites, tau, -synuclein, and TDP43 in different types of human neurons. We will determine molecular mechanism that autophagy controls neuronal functions by using human induced neurons (aim 1) and neuroprotective function of autophagy in controlling protein homeostasis of -synuclein, tau, APP/metabolites, and TDP-43 by using human iN cells (aim 2). Our study is expected to elucidate autophagy functions in human neurons and shed light on the mechanism for the accumulation and spreading of disease proteins underlying the selective neuron vulnerability in major neurodegenerative diseases with dementia.