Our goal is to elucidate neuroprotective mechanisms of autophagy and harness the knowledge to develop therapeutic strategies for neurodegenerative diseases. Autophagy is a major catabolic process involving the synthesis, transport, and degradation of autophagosomes, which sequester and recycle large molecular complexes, protein aggregates, and cellular organelles through lysosome pathway. Human neuropathological and genetic studies suggest dysfunctional autophagy-lysosome pathway as a common pathogenic pathway for Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). My lab pioneers in the study of autophagy in neurons. We reported the disruption of specific autophagy functions in animal and cell models of AD, PD, and ALS. We and others showed that neuronal autophagy is compartmentalized, and that different neuron types have distinct vulnerability to autophagy deficiency in the brain. Furthermore, basal autophagy is selective and mediated by autophagy receptors. By characterizing dopamine neuron (DA)-specific autophagy knockout and SYNJ1 mutant mice, we showed an interplay between autophagy, synaptic vesicle (SV) trafficking, and regulation of αSyn homeostatic levels in age and neuron-type specific manners. Moreover, our recent study has revealed a critical role for microglial autophagy in the clearance of neuron-released αSyn and protection of DA neurons in mice (we termed synucleinphagy). Therefore, we propose to elucidate cell-type specific autophagy pathways (neuron vs. microglia) under physiological (young and old) and pathological conditions (PD). We will perform a systemic study that integrates multiple genetic mutant lines of mice, human induced neuron lines (hiN), quantitative proteomics, and molecular and cell biology to identify autophagy cargo and receptors in neurons and microglia. We will identify novel autophagy cargo and receptors in mediating autophagy functions and SV trafficking in an age and neuron-type (e.g.DA neuron) specific manner. We will determine distinct pathways of autophagy regulation between neuron and microglia. Our study is expected to contribute to the understanding of different mechanism of Syn degradation. Our study will pave the way to identify novel therapeutic targets of autophagy in the treatment of PD or synucleinopathies.