Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases.
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.
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA.
Brian
B
Spencer
Rewati
R
Potkar
Margarita
M
Trejo
Edward
E
Rockenstein
Christina
C
Patrick
Ryan
R
Gindi
Anthony
A
Adame
Tony
T
Wyss-Coray
Eliezer
E
Masliah
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D001921:Brain / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006801:Humans; D020961:Lewy Body Disease / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000502:physiology; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D051844:alpha-Synuclein