Lewy body disease (LBD) is a group of disorders characterized by alpha-synuclein (alpha-syn) accumulation and parkinsonism. During the previous period, the objective was to understand the mechanisms by which (3- synuclein ((3-syn)?a close homologue to alpha-syn?blocks a-syn aggregation and might have a role in the treatment of degenerative disorders such as Alzheimer's disease (AD) and LBD. Both p-syn and antibodies against alpha-syn target alpha-syn aggregates for clearance probably via autophagy, a process of degradation and recycling of cellular constituents. Alterations in autophagy might play a role in the pathogenesis of AD and LBD, and might represent a target for treatment development. The objectives of this renewal application are: i) to gain new knowledge as to the involvement of the autophagy pathways in the mechanisms of neurodegeneration in LBD, ii) to develop new experimental therapies for LBD by targeting the autophagy pathways and iii) to better understand the involvement of the autophagy pathways in the mechanisms of asyn clearance mediated by immunotherapy. We propose the following aims:
AIM 1. Characterize in vivo the contribution of selected molecular components of the autophagy pathway to the pathogenesis of LBD.
AIM 2. Investigate in in vivo models of alpha-synucleinopathy the therapeutic and neuroprotective effects of activators of the autophagy pathway.
AIM 3. Better understand the cellular mechanisms involved in the clearance of toxic alpha-syn aggregates via specific antibodies.
AIM 4. Determine in immunized animals, the contribution of autophagy to the molecular mechanisms involved in alpha-syn clearance. alpha-Syn transgenic mice will be crossed with mice either deficient in or transgenic for components of the autophagy pathway (e.g. Beclinl, LAMP2, mTor). Mice will be treated with stimulators of autophagy (rapamycin, immunotherapy) and analyzed behaviorally, biochemically and neuropathologically. Studies will be complemented with primary neuronal cultures treated with lentiviral vectors and analyzed for markers of autophagy. Better understanding the autophagic pathways involved in alpha-syn clearance is of central importance toward elucidating the pathogenesis of LBD and developing new treatments for these conditions. Thus, enhancing autophagy and lysosomal degradation of alpha-syn may represent a promising therapeutical strategy for the treatment not only for LBD but also for AD.
|Gillman, Alan L; Lee, Joon; Ramachandran, Srinivasan et al. (2016) Small molecule NPT-440-1 inhibits ionic flux through AÎ²1-42 pores: Implications for Alzheimer's disease therapeutics. Nanomedicine 12:2331-2340|
|Kratter, Ian H; Zahed, Hengameh; Lau, Alice et al. (2016) Serine 421 regulates mutant huntingtin toxicity and clearance in mice. J Clin Invest 126:3585-97|
|Rockenstein, Edward; Clarke, Jennifer; Viel, Catherine et al. (2016) Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinson's disease. Hum Mol Genet 25:2645-2660|
|Kim, Changyoun; Lee, He-Jin; Masliah, Eliezer et al. (2016) Non-cell-autonomous Neurotoxicity of Î±-synuclein Through Microglial Toll-like Receptor 2. Exp Neurobiol 25:113-9|
|Price, Diana L; Rockenstein, Edward; Mante, Michael et al. (2016) Longitudinal live imaging of retinal Î±-synuclein::GFP deposits in a transgenic mouse model of Parkinson's Disease/Dementia with Lewy Bodies. Sci Rep 6:29523|
|Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia et al. (2016) HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders. Neurobiol Dis 86:154-69|
|Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-Î², Î±-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89|
|Kim, Eunhee; Wang, Bin; Sastry, Namratha et al. (2016) NEDD4-mediated HSF1 degradation underlies Î±-synucleinopathy. Hum Mol Genet 25:211-22|
|de Wilde, Martijn C; Overk, Cassia R; Sijben, John W et al. (2016) Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement 12:633-44|
|Kim, Changyoun; Lv, Guohua; Lee, Jun Sung et al. (2016) Exposure to bacterial endotoxin generates a distinct strain of Î±-synuclein fibril. Sci Rep 6:30891|
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