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J Neurosci. 2009 Oct 28;29(43):13578-88./ E8 U) y; o* A2 A' Z$ x

/ Q$ L& i3 O2 v1 zBeclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases.! c# J7 _) k0 F* }- M& r, H2 R
Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E.
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Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA.5 V9 Q- y3 B0 N* W+ i/ ~4 C3 w) ^; H

' `0 N1 a& h8 {5 {0 {6 b7 F5 b- @# c. ZAccumulation 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.

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