[en] 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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Scheiblich, Hannah; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Dansokho, Cira; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Mercan, Dilek; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Schmidt, Susanne V ; Institute of Innate Immunity, University of Bonn Medical Center, 53127 Bonn, Germany
Bousset, Luc; Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, 92265 Fontenay-aux-Roses, France
Wischhof, Lena; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Eikens, Frederik; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Odainic, Alexandru; Institute of Innate Immunity, University of Bonn Medical Center, 53127 Bonn, Germany
Spitzer, Jasper; Institute of Innate Immunity, University of Bonn Medical Center, 53127 Bonn, Germany
Griep, Angelika ; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Schwartz, Stephanie; Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology, University of Bonn Medical Center, 53127 Bonn, Germany
Bano, Daniele; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Latz, Eicke; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany, Institute of Innate Immunity, University of Bonn Medical Center, 53127 Bonn, Germany
Melki, Ronald; Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, 92265 Fontenay-aux-Roses, France
HENEKA, Michael ; University of Bonn Medical Center > Department of Neurodegenerative Disease and Geriatric Psychiatry/Neurology ; German Center for Neurodegenerative Diseases (DZNE) ; University of Massachusetts Medical School > Divison of Infectious Diseases and Immunology
The authors would like to thank Prof. Dr. Manuela Neumann and the Tübingen Brain Bank as well as Prof. Dr. Annett Halle and the DZNE Brain Bank Bonn for kindly providing human brain samples. We thank Dr. Pawel Tacik, Dr. Dr. Sergio Castro-Gomez, and Dr. Sarah Bernsen for providing us with patients’ blood samples. Many thanks to the patients and their spouses who have volunteered to donate blood. The authors would like to thank Maike Kreutzenbeck and Ulrike Stube for their support regarding RNA isolation and preparation for sequencing. We thank the DZNE light microscope facility (LMF) for providing microscopes and advice and the DZNE Image and Data Analysis Facility (IDAF) for providing analysis computers and software. We thank the Flow Cytometry Core Facility for their help regarding cell sorting and the NGS Core Facility of the University Hospital Bonn for the library preparing and the generation of the sequencing data. We would like to thank the Microscopy Core Facility of the Medical Faculty at the University of Bonn for providing support and instrumentation funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project number 388171357 .This work was supported by funding from the Joint Program on Neurodegenerative Diseases (JPND) to M.T.H. and R.M. (01ED1603) and the Gemeinn?tzige Hertie Stiftung to H.S. (P1200007); M.T.H. received further fundings from a NIH grant (R01 AG059752-02) and from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy EXC2151-390873048; R.M. and L.B. also received support from the European Union's Horizon 2020 research and innovation program and EFPIA Innovative Medicines Initiative 2 grant agreement 821522 (PD-MitoQUANT) and Parkinson UK. The authors would like to thank Prof. Dr. Manuela Neumann and the T?bingen Brain Bank as well as Prof. Dr. Annett Halle and the DZNE Brain Bank Bonn for kindly providing human brain samples. We thank Dr. Pawel Tacik, Dr. Dr. Sergio Castro-Gomez, and Dr. Sarah Bernsen for providing us with patients? blood samples. Many thanks to the patients and their spouses who have volunteered to donate blood. The authors would like to thank Maike Kreutzenbeck and Ulrike Stube for their support regarding RNA isolation and preparation for sequencing. We thank the DZNE light microscope facility (LMF) for providing microscopes and advice and the DZNE Image and Data Analysis Facility (IDAF) for providing analysis computers and software. We thank the Flow Cytometry Core Facility for their help regarding cell sorting and the NGS Core Facility of the University Hospital Bonn for the library preparing and the generation of the sequencing data. We would like to thank the Microscopy Core Facility of the Medical Faculty at the University of Bonn for providing support and instrumentation funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project number 388171357. H.S. and M.T.H. designed all experiments; H.S. performed experiments and analyzed data with assistance of C.D. F.E. S.S. A.G. and M.T.H.; L.B. and R.M. generated and characterized all ?-synuclein assemblies and provided advice; S.V.S. A.O. and J.S. performed and analyzed RNA sequencing data; L.W. and D.B. performed Seahorse experiments and mitochondrial quantifications; D.M. performed in vivo 2-photon imaging with assistance of H.S. and C.D.; H.S. and M.T.H. wrote the manuscript with input from all co-authors. Michael T. Heneka serves as an advisory board member at IFM Therapeutics, Alector and Tiaki. He received honoraria for oral presentations from Novartis, Roche, and Biogen. The other authors declare that there is no conflict of interest with regard to the experimental part of this study.This work was supported by funding from the Joint Program on Neurodegenerative Diseases ( JPND ) to M.T.H. and R.M. (01ED1603) and the Gemeinnützige Hertie Stiftung to H.S. ( P1200007 ); M.T.H. received further fundings from a NIH grant ( R01 AG059752-02 ) and from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy EXC2151-390873048; R.M. and L.B. also received support from the European Union’s Horizon 2020 research and innovation program and EFPIA Innovative Medicines Initiative 2 grant agreement 821522 (PD-MitoQUANT) and Parkinson UK .
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