Determining neuroprotective autophagy functions using different types of human neurons

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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.