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Updated: Oct 19, 2025
Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes
Hannah Scheiblich1, Cira Dansokho1, Dilek Mercan1
1Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
Abstract:
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.
Insights
Microglia form networks to transfer and degrade alpha-synuclein (α-syn) fibrils, a key process in neurodegenerative diseases. This network formation aids clearance, but is impaired by LRRK2 mutations.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are central nervous system (CNS) immune cells that respond to misfolded proteins like alpha-synuclein (α-syn).
- Dysfunctional α-syn clearance is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate how microglia manage and clear α-syn fibrils.
- To understand the role of intercellular communication in α-syn handling.
Main Methods:
- Exposure of microglia to α-syn fibrils in vitro.
- Assessment of F-actin-dependent intercellular connections.
- Analysis of α-syn transfer and degradation.
- Investigation of LRRK2 G2019S mutation effects.
- Validation in organotypic slice cultures and patient neuropathology.
Main Results:
- Microglia form F-actin-dependent networks to transfer α-syn fibrils to naive cells.
- Intercellular transfer facilitates rapid and effective degradation of α-syn.
- Reduced α-syn burden improves microglial inflammatory profile and survival.
- This clearance mechanism is impaired in cells with LRRK2 G2019S mutation.
Conclusions:
- Microglia establish a functional intercellular network for efficient clearance of pathogenic α-syn.
- This network-based degradation strategy is crucial for mitigating α-syn toxicity.
- Impairment of this network by LRRK2 mutations highlights a potential therapeutic target.
