Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

Hannah Scheiblich,Cira Dansokho,Dilek Mercan,Susanne V Schmidt,Luc Bousset,Lena Wischhof,Frederik Eikens,Alexandru Odainic,Jasper Spitzer,Angelika Griep,Stephanie Schwartz,Daniele Bano,Eicke Latz,Ronald Melki,Michael T Heneka

doi:10.1016/j.cell.2021.09.007

Abstract

SummaryMicroglia 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.

Highlights

Several synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies (LB) that are rich in an aggregated form of the protein a-synuclein (a-syn) (Spillantini et al, 1997). a-syn is a 14 kDa protein with no defined structure (Weinreb et al, 1996) that is primarily produced in neurons
Even though we found that untreated microglia formed some intercellular connections, a-syn induced the formation of those microglia-to-microglia connections, thereby increasing the number of microglial cell-to-cell contacts (Figure S1L)
Mutation were not able to rescue neighboring cells, thereby inducing their own reactive oxygen species (ROS) level (Figure 5I;Figure S6D). These results indicate that dysregulated a-syn degradation in LRRK2 mutant microglia may represent one pathogenic factor by which mutations within LRRK2 cause familial PD

Summary

Introduction

Several synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies (LB) that are rich in an aggregated form of the protein a-synuclein (a-syn) (Spillantini et al, 1997). a-syn is a 14 kDa protein with no defined structure (Weinreb et al, 1996) that is primarily produced in neurons. Several synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies (LB) that are rich in an aggregated form of the protein a-synuclein (a-syn) (Spillantini et al, 1997). A-syn is a 14 kDa protein with no defined structure (Weinreb et al, 1996) that is primarily produced in neurons. The monomeric form of the protein progressively forms oligomeric structures and insoluble fibrillar assemblies that, together with crowded organellar components (Shahmoradian et al, 2019), accumulate in LBs. Overexpression of a-syn or mutations in the SNCA gene that encodes for a-syn cause progressive locomotor deficits and loss of dopaminergic neurons in the substantia nigra (Blesa and Przedborski, 2014). Increasing the clearance of a-syn and lowering the accompanying protein accumulation may be a promising therapeutic strategy for the treatment of synucleinopathies

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Conclusion