VPS35 is a major component of retromer that is essential for selective endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is implicated in the pathogenesis of Alzheimer's disease (AD) as well as Parkinson's disease (PD), because mutations in Vps35 and SorLA (a cargo of retromer) genes have been identified in the late-onset PD and AD patients, respectively. Thus, it is of considerable interest to investigate how VPS35/retromer deficiency contributes to neurodegeneration. Three hypotheses will be tested in this proposal. The first hypothesis is that VPS35/retromer expression in pyramidal neurons is critical to prevent AD-relevant neuropathology. The second hypothesis is that VPS35/retromer deficient neurons are impaired in BACE1 retrograde trafficking, thus increasing BACE1 activity and promoting dendritic and axonal degeneration. The third hypothesis is that VPS35/retromer deficient microglial cells are hypersensitive to TNF? family cytokines, releasing excessive proinflammatory cytokines and promoting brain inflammation and neurodegeneration. Both hypotheses are supported by our publications and recent preliminary studies. We hope that the proposed studies will not only establish novel cellular functions of VPS35/retromer in preventing hyper-activation of BACE1 and microglia, but also shed new lights into pathogenesis of neurodegenerative disorders, such as AD and PD. We also hope that this research may point to new therapeutic strategies for the treatment of these disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01AG045781-01A1
Application #
8708256
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Huang, Zhihui; Hu, Jinxia; Pan, Jinxiu et al. (2016) YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation. Development 143:2398-409
Huang, Zhihui; Sun, Dong; Hu, Jin-Xia et al. (2016) Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex. J Neurosci 36:5833-49
Huang, Zhihui; Wang, Ying; Hu, Guoqing et al. (2016) YAP Is a Critical Inducer of SOCS3, Preventing Reactive Astrogliosis. Cereb Cortex 26:2299-310
Tang, Fu-Lei; Liu, Wei; Hu, Jin-Xia et al. (2015) VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function. Cell Rep 12:1631-43
Wu, Haitao; Barik, Arnab; Lu, Yisheng et al. (2015) Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation. Elife 4:
Tang, Fu-Lei; Erion, Joanna R; Tian, Yun et al. (2015) VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for α-Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease. J Neurosci 35:10613-28
Tian, Yun; Tang, Fu-Lei; Sun, XiangDong et al. (2015) VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation. Mol Brain 8:70
Liu, Wei; Tang, Fu-Lei; Erion, Joanna et al. (2014) Vps35 haploinsufficiency results in degenerative-like deficit in mouse retinal ganglion neurons and impairment of optic nerve injury-induced gliosis. Mol Brain 7:10