{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Spencer B"],"funding":["NIA NIH HHS","NCRR NIH HHS","NIEHS NIH HHS"],"pagination":["13578-88"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC2812014"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(43)"],"pubmed_abstract":["Accumulation of the synaptic protein alpha-synuclein (alpha-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD), a heterogeneous group of disorders with dementia and parkinsonism, where Alzheimer's disease and PD interact. Accumulation of alpha-syn in these patients might be associated with alterations in the autophagy pathway. Therefore, we postulate that delivery of beclin 1, a regulator of the autophagy pathway, might constitute a strategy toward developing a therapy for LBD/PD. Overexpression of alpha-syn from lentivirus transduction in a neuronal cell line resulted in lysosomal accumulation and alterations in autophagy. Coexpression of beclin 1 activated autophagy, reduced accumulation of alpha-syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and alpha-syn accumulation were partially blocked by 3-MA and completely blocked by bafilomycin A1. In contrast, rapamycin enhanced the effects of beclin 1. To evaluate the potential effects of activating autophagy in vivo, a lentivirus expressing beclin 1 was delivered to the brain of a alpha-syn transgenic mouse. Neuropathological analysis demonstrated that beclin 1 injections ameliorated the synaptic and dendritic pathology in the tg mice and reduced the accumulation of alpha-syn in the limbic system without any significant deleterious effects. This was accompanied by enhanced lysosomal activation and reduced alterations in the autophagy pathway. Thus, beclin 1 plays an important role in the intracellular degradation of alpha-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD."],"journal":["The Journal of neuroscience : the official journal of the Society for Neuroscience"],"pubmed_title":["Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases."],"pmcid":["PMC2812014"],"funding_grant_id":["P41 RR004050-217823","AG022074","P01 AG010435-120006","P01 AG010435","P01 ES016738","P50 AG005131","P01 AG010435-160006","AG18440","AG5131","P50 AG005131-16S40023","R01 AG018440","R01 AG030144","R37 AG018440","R37 AG018440-09","P50 AG005131-190023","P41 RR004050","AG10435","P01 AG022074","P01 ES016738-029003","P01 AG022074-070009"],"pubmed_authors":["Rockenstein E","Patrick C","Adame A","Gindi R","Spencer B","Potkar R","Trejo M","Masliah E","Wyss-Coray T"],"additional_accession":[]},"is_claimable":false,"name":"Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases.","description":"Accumulation of the synaptic protein alpha-synuclein (alpha-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD), a heterogeneous group of disorders with dementia and parkinsonism, where Alzheimer's disease and PD interact. Accumulation of alpha-syn in these patients might be associated with alterations in the autophagy pathway. Therefore, we postulate that delivery of beclin 1, a regulator of the autophagy pathway, might constitute a strategy toward developing a therapy for LBD/PD. Overexpression of alpha-syn from lentivirus transduction in a neuronal cell line resulted in lysosomal accumulation and alterations in autophagy. Coexpression of beclin 1 activated autophagy, reduced accumulation of alpha-syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and alpha-syn accumulation were partially blocked by 3-MA and completely blocked by bafilomycin A1. In contrast, rapamycin enhanced the effects of beclin 1. To evaluate the potential effects of activating autophagy in vivo, a lentivirus expressing beclin 1 was delivered to the brain of a alpha-syn transgenic mouse. Neuropathological analysis demonstrated that beclin 1 injections ameliorated the synaptic and dendritic pathology in the tg mice and reduced the accumulation of alpha-syn in the limbic system without any significant deleterious effects. This was accompanied by enhanced lysosomal activation and reduced alterations in the autophagy pathway. Thus, beclin 1 plays an important role in the intracellular degradation of alpha-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.","dates":{"release":"2009-01-01T00:00:00Z","publication":"2009 Oct","modification":"2020-08-20T07:07:11Z","creation":"2019-03-27T00:28:10Z"},"accession":"S-EPMC2812014","cross_references":{"pubmed":["19864570"],"doi":["10.1523/JNEUROSCI.4390-09.2009","10.1523/jneurosci.4390-09.2009"]}}