Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes
Open accessAbstract
Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic α-syn clearance.
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The phagocytic activity of microglia is crucial for the removal of Aβ, tau, and α-synuclein.
“The phagocytic activity of microglia is crucial for the removal of Aβ,94 tau,95 and α-synuclein.96”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [96]
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BackgroundMicrobiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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Liu, Y.-J., Ding, Y., Yin, Y.-Q., Xiao, H., Hu, G., & Zhou, J.-W. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2210643120 · Cited by 14 · see citing works
- Authors
- Scheiblich, H., Dansokho, C., Mercan, D., Schmidt, S. V., Bousset, L., Wischhof, L., Eikens, F., Odainic, A., Spitzer, J., Griep, A., Schwartz, S., Bano, D., Latz, E., Melki, R., & Heneka, M. T.
- Affiliations
- University of Bonn (DE)
- Centre National de la Recherche Scientifique (FR)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Heneka, Michael T.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 184
- Issue
- 20
- Pages
- 5089-5106.e21
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8527836
- OpenAlex
- W3199862549
- Cited by
- 360
- References
- 74
- Citations by year
- 2026: 59 · 2025: 84 · 2024: 76 · 2023: 67 · 2022: 68 · 2021: 5
- FWCI
- 21.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- Funders
- EU Joint Programme – Neurodegenerative Disease Research
- Agence Nationale de la Recherche (ANR-11-INBS-0011)
- National Institute on Aging (R01AG059752)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- microglia, alpha-synuclein, tunneling nanotubes, intercellular transfer, LRRK2 G2019S mutation, microglial inflammation, microglial survival, neurodegeneration, organotypic slice cultures
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Actins, Aged, Aged, 80 and over, Animals, Cytoskeleton, Female, Humans, Inflammation, Male, Mice, Inbred C57BL, Mitochondria, Down-Regulation, Apoptosis, Reactive Oxygen Species, Microglia, Cell Membrane Structures, Nanotubes, Mice, alpha-Synuclein, Transcriptome, Proteolysis, Protein Aggregates
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