Neuronal Autophagy: a Cell-Autonomous Protection Mechanism

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Our long-term goal is to understand neuroprotective mechanisms of autophagy and identify therapeutic targets of autophagy to treat neurodegenerative diseases associated with intraneuronal protein aggregates. The physiological function of autophagy in neuron is to maintain metabolic homeostasis and serve as quality control through constant degradation. Importantly, the constitutive autophagy in neurons shows high selectivity, targeting specific protein and organelle cargo to the lysosomal degradation. However, the molecular mechanism for the selective autophagy remains poorly characterized in neurons. Increasing evidence shows that selective autophagy is mediated through a family of proteins called autophagy receptors, which are characterized by the ability to recognize degradation signals on cargo proteins and also bind LC3/GABARAP proteins on the forming autophagosome. Our current goal is to understand the physiological function and selective nature of autophagy in neurons and dissect the molecular mechanism whereby selective autophagy clears disease related proteins particularly related to Alzheimer’s disease (AD). AD is characterized pathologically by the extracellular amyloid plaques and intraneuronal neurofibrillary tau tangles. Recent failures of AD clinical trials show the urgency to have deeper understanding of the pathogenic pathways and develop novel therapeutic strategies of AD. Indeed, multiple lines of evidence suggest that basal autophagy prevents the accumulation of phosphorylated tau (p-tau). Furthermore, our lab and others suggests that autophagy selectively degrades amyloid β precursor protein (APP) and its metabolites (e.g. C- terminal fragments or CTFs and Aβ). We hypothesize that autophagy selectively removes toxic tau species and APP/APP metabolites through specific autophagy receptors. Given increasing evidence implicating autophagy in controlling the levels of p-Tau, APP and its metabolites, we propose that targeting selective autophagy pathway offers a novel disease-modifying strategy for the treatment of AD. We propose the following Aims to test above hypothesis: Aim 1. Determine the physiological function and the selective nature of autophagy in neurons. Aim 2. Examine the role for selective autophagy in the regulation of tau homeostasis and tauopathies. Aim 3. Determine the mechanism for selective autophagy in the clearance of APP and its metabolites. We seek to establish molecular basis for how selective autophagy regulates the homeostasis of the two most important AD related proteins, phospho-tau and APP (and its metabolites) in CNS; our study is expected to provides insight into the pathogenesis of AD and assist in the development of novel disease-modifying strategy for AD treatment.