J Neurosci. 2009 Oct 28;29(43):13578-88./ ?" \9 A) ^$ n- |
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Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. . ^3 S' _, W4 B( v4 d! l; r' cSpencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E.% p+ g7 h0 F& E; n5 r4 }) X
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Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA. , \0 Q) [5 C7 `# V7 ^" P7 K: [( { 4 s4 R& B6 O' O) S$ ~$ hAccumulation 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.作者: lpzhdm 时间: 2009-10-30 22:38