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 ? precursor protein (APP) and its metabolites (e.g. C- terminal fragments or CTFs and A?). 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.

Public Health Relevance

We propose to determine the mechanism for how autophagy selectively degrades protein cargo in neurons and the molecular basis for autophagic clearance 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060123-14
Application #
10083233
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Mcgavern, Linda
Project Start
2008-04-01
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
14
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Wang, Changhe; Kang, Xinjiang; Zhou, Li et al. (2018) Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson's disease-like pathology. Nat Commun 9:81
Wu, Shuai; He, Yunjiao; Qiu, Xianxiu et al. (2018) Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking. Proc Natl Acad Sci U S A 115:E5669-E5678
Sheehan, Patricia; Yue, Zhenyu (2018) Deregulation of autophagy and vesicle trafficking in Parkinson's disease. Neurosci Lett :
Deng, Zhiqiang; Purtell, Kerry; Lachance, Veronik et al. (2017) Autophagy Receptors and Neurodegenerative Diseases. Trends Cell Biol 27:491-504
Deng, Zhiqiang; Sheehan, Patricia; Chen, Shi et al. (2017) Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease? Mol Neurodegener 12:90
Wold, Mitchell S; Lim, Junghyun; Lachance, Véronik et al. (2016) ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington's disease models. Mol Neurodegener 11:76
Zhang, Jinglan; Lachance, Véronik; Schaffner, Adam et al. (2016) A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects. PLoS Genet 12:e1005848
Lim, Junghyun; Yue, Zhenyu (2015) Neuronal aggregates: formation, clearance, and spreading. Dev Cell 32:491-501
Lim, Junghyun; Lachenmayer, M Lenard; Wu, Shuai et al. (2015) Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet 11:e1004987
Ouseph, Madhu M; Huang, Yunjie; Banerjee, Meenakshi et al. (2015) Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. Blood 126:1224-33

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