Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases
Open accessAbstract
Accumulation of the synaptic protein α-synuclein (α-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 α-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 α-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 α-syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and α-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 α-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 α-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 α-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.
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Mutant forms of synuclein and oligomers are dependent on the autophagy-lysosome pathway for their clearance.
“However, mutant forms of synuclein and oligomers are dependent on the autophagy–lysosome pathway for their clearance4–6.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [5]
Several lines of evidence indicate a role for autophagy in the regulation of synuclein homeostasis, suggesting that dysfunctional autophagic clearance may contribute to the development of synuclein inclusions.
“Several lines of evidence indicate a role for autophagy in the regulation of synuclein homeostasis5,6,15, suggesting that dysfunctional autophagic clearance may contribute to the development of synuclein inclusions.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [5]
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- Authors
- Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R., Adame, A., Wyss-Coray, T., & Masliah, E.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Masliah, Eliezer
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-10-28
- Volume
- 29
- Issue
- 43
- Pages
- 13578-13588
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2812014
- OpenAlex
- W2088198588
- Cited by
- 595
- References
- 72
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 19 · 2023: 30 · 2022: 29 · 2021: 29 · 2020: 41 · 2019: 58 · 2018: 35 · 2017: 42 · 2016: 36 · 2015: 55 · 2014: 44 · 2013: 47 · 2012: 42
- FWCI
- 20.70
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-12-03)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG5131, AG‐022074, AG‐18440, AG10435)
- National Institute on Aging (P01AG010435, R37AG018440, R01AG018440, P50AG005131, AG-5131, AG022074, AG 18440, R01AG030144, P01AG022074, AG10435)
- National Institute of Environmental Health Sciences (P01ES016738)
- National Center for Research Resources (P41RR004050)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Beclin-1, alpha-synuclein, Parkinson's disease, Lewy body disease, autophagy, lysosomal accumulation, LC3, bafilomycin A1, rapamycin, 3-methyladenine, transgenic mouse model, synaptic pathology, limbic system, neurodegeneration
- MeSH terms
- Beclin-1, Animals, Autophagy, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Nerve Degeneration, Neurons, Parkinson Disease, Signal Transduction, Gene Transfer Techniques, Lewy Body Disease, Cell Line, Tumor, Apoptosis Regulatory Proteins, Mice, Rats, alpha-Synuclein
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