Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway
Open accessAbstract
Cytoplasmic deposition of alpha-synuclein aggregates is a common pathological feature of many neurodegenerative diseases. Strong evidence for the causative role of alpha-synuclein in these disorders is provided by genetic linkage between this gene and familial Parkinson's disease and by neurodegeneration in transgenic animals that overexpress this protein. In particular, it has been hypothesized that the accumulation of nonfibrillar oligomers of alpha-synuclein, which serve as intermediates for fibrillar inclusion body formation, causes neurodegeneration. However, little is known about how cells handle potentially toxic protein aggregates. Here we demonstrate that cells are capable of clearing preformed alpha-synuclein aggregates via the lysosomal degradation pathway. Consequently, blocking this pathway causes the accumulation of the aggregates in non-neuronal cells, differentiated neuroblastoma cells, and primary cortical neurons. This aggregate clearance occurs in an aggregation stage-specific manner; oligomeric intermediates are susceptible to clearance, whereas mature fibrillar inclusion bodies are not. Neutralization of the acidic compartments leads to the accumulation of alpha-synuclein aggregates and exacerbates alpha-synuclein toxicity in postmitotic neuronal cells, suggesting that the accumulation of oligomeric intermediates may be an important event leading to alpha-synuclein-mediated cell death. These results suggest that enhancing lysosomal function may be a poten…
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Extracellular α-synuclein aggregates can interact with microglia via TLR2 to activate the LRRK2-NFATc2 pathway and produce a pro-inflammatory phenotype, and can also interact with other receptors to initiate LRRK2-dependent aggregate phagocytosis and clearance via lysosomal pathways.
“Extracellular α-synuclein aggregates may interact with microglia in at least two different ways: on one hand, they may stimulate TLR2 to activate the LRRK2-NFATc2 pathway and produce a pro-inflammatory phenotype, as shown in the present study; on the other, they can also interact with other receptors to initiate LRRK2-dependent aggregate phagocytosis (48) and clearance via lysosomal pathways (49,”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [49]
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- Authors
- Lee, H.-J., Khoshaghideh, F., Patel, S., & Lee, S.-J.
- Affiliations
- Parkinson's Institute and Clinical Center (US)
- Seoul National University (KR)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-02-25
- Volume
- 24
- Issue
- 8
- Pages
- 1888-1896
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730405
- OpenAlex
- W2117626437
- Cited by
- 445
- References
- 3
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 33 · 2023: 11 · 2022: 22 · 2021: 21 · 2020: 34 · 2019: 23 · 2018: 15 · 2017: 22 · 2016: 18 · 2015: 14 · 2014: 19 · 2013: 18 · 2012: 23
- FWCI
- 11.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- Directorate for Biological Sciences
- National Cancer Institute (R01CA094089)
- National Institute of Child Health and Human Development
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, oligomeric intermediates, lysosomal degradation, protein aggregate clearance, Parkinson's disease, Lewy body disease, neurodegeneration, lysosomal acidification, neuroblastoma cells, cortical neurons
- MeSH terms
- Animals, Cell Compartmentation, Cell Survival, Cells, Cultured, Inclusion Bodies, Chlorocebus aethiops, Dimethyl Sulfoxide, Enzyme Inhibitors, Humans, Lysosomes, Nerve Tissue Proteins, Neuroblastoma, Neurons, Rotenone, Time Factors, Transfection, Uncoupling Agents, Gene Expression, Cell Death, Rats, Sprague-Dawley, COS Cells, Neurodegenerative Diseases, Macromolecular Substances, Rats, Synucleins, alpha-Synuclein
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