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The Journal of Neuroscience, October 28, 2009, 29(43):13578-13588; doi:10.1523/JNEUROSCI.4390-09.2009

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Neurobiology of Disease
Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in -Synuclein Models of Parkinson's and Lewy Body Diseases

Brian Spencer,¹ Rewati Potkar,¹ Margarita Trejo,¹ Edward Rockenstein,¹ Christina Patrick,¹ Ryan Gindi,¹ Anthony Adame,¹ Tony Wyss-Coray,³ and Eliezer Masliah^1,2

Departments of ¹Neurosciences and ²Pathology, University of California, San Diego, La Jolla, California 92093, and ³Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305

Correspondence should be addressed to Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624. Email: emasliah{at}ucsd.edu

Accumulation of the synaptic protein -synuclein (-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 -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 -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 -syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and -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 -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 -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 -syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.

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Received Sept. 4, 2009; accepted Sept. 15, 2009.

Correspondence should be addressed to Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624. Email: emasliah{at}ucsd.edu

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