The overarching goal of this application is to advance our understanding of neuroprotective pathways of autophagy and develop new strategies of targeting autophagy for the treatment of neurodegenerative diseases. While the cellular process of autophagy is evolutionarily conserved, the regulation of autophagy in neurons and neurodegeneration is poorly understood. The lack of understanding of autophagy regulation in neurons and CNS diseases has impeded the development of therapeutic strategies for targeting autophagy. Based on our studies and others in multiple genetic mouse models for autophagy and diseases, our central hypothesis is that basal autophagy is tightly regulated and neuroprotective by continuous clearance of toxic proteins and damaged organelles;the functions of autophagy genes intersect with various neuronal pathways;autophagy regulates the homeostasis of many disease-related proteins, and therefore, constitute an important disease modifying cellular pathway. We have a long-standing interest in understanding Beclin1/Vps34 (class III PtdIns-3-kinase!, which is a key regulator of autophagy. Our earlier reports suggest that beclin1 is a haploinsufficient tumor suppressor and involved in excitotoxicity (Lurcher)-induced hyperactive autophagy. Emerging evidence demonstrates a neuroprotective role of beclin1 in clearing disease-related proteins, including APP metabolites, A-synuclein and mutant ataxin in the CNS. Interestingly, our preliminary study in genetic models suggests that reduced beclin1 expression is associated with an age-dependent pathological protein accumulation in mouse brains. We previously reported multiple Beclin1/Vps34 complexes containing different binding partners such as UVRAG, Atg14L and Rubicon that have distinct functions in autophagy regulation. Our structural and functional analysis started to reveal the molecular basis underlying the interactions between the binding partners, providing valuable information to develop new strategies for enhancing autophagy and the neuroprotective function of autophagy. We hypothesize that Beclin1/Vps34 activity plays a critical role in controlling the disease protein clearance, and that the activity offers a novel drug target for modulating autophagic activity and developing potential therapeutic treatment of proteinopathies. In this application we propose to determine (1) autophagy gene beclin1 is a haploinsufficient suppressor of pathological modifications of CNS disease proteins in mouse models;(2) the molecular mechanism whereby Beclin1/Vps34-mediated autophagy controls the modifications and clearance of the disease proteins;and (3) determine molecular/structural basis for enhancing Beclin1/Vps34-mediated autophagy that protects against accumulation of pathological protein accumulation. We anticipate that accomplishment of the plan will yield insight into the neuroprotective mechanism of autophagy, and importantly, obtain valuable information for developing autophagy-modulating therapeutics to treat proteinopathy diseases in CNS.
The ultimate goal of our proposal is to advance our understanding of neuroprotective pathways of autophagy and develop new strategies of targeting autophagy for the treatment of neurodegenerative diseases that are associated with disease protein aggregation.
|McKnight, Nicole C; Zhong, Yun; Wold, Mitchell S et al. (2014) Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex. PLoS Genet 10:e1004626|
|Yamamoto, Ai; Yue, Zhenyu (2014) Autophagy and its normal and pathogenic states in the brain. Annu Rev Neurosci 37:55-78|
|Lu, Jiahong; He, Liqiang; Behrends, Christian et al. (2014) NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity. Nat Commun 5:3920|
|Pan, Ping-Yue; Yue, Zhenyu (2014) Genetic causes of Parkinson's disease and their links to autophagy regulation. Parkinsonism Relat Disord 20 Suppl 1:S154-7|
|Yang, Yi; Coleman, Michael; Zhang, Lihui et al. (2013) Autophagy in axonal and dendritic degeneration. Trends Neurosci 36:418-28|
|Dehay, Benjamin; Martinez-Vicente, Marta; Caldwell, Guy A et al. (2013) Lysosomal impairment in Parkinson's disease. Mov Disord 28:725-32|
|Hernandez-Gea, Virginia; Ghiassi-Nejad, Zahra; Rozenfeld, Raphael et al. (2012) Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142:938-46|
|Li, Xiaohua; He, Liqiang; Che, Ka Hing et al. (2012) Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat Commun 3:662|
|Yu, Zhigang; Wang, Adrienne M; Adachi, Hiroaki et al. (2011) Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet 7:e1002321|
|Funderburk, Sarah F; Marcellino, Bridget K; Yue, Zhenyu (2010) Cell "self-eating" (autophagy) mechanism in Alzheimer's disease. Mt Sinai J Med 77:59-68|
Showing the most recent 10 out of 17 publications