Journal Article

DZNE-2021-01507

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.

Scheiblich, H. (First author)DZNE* ; Dansokho, C.DZNE* ; Mercan, D.DZNE* ; Schmidt, S. V. ; Bousset, L. ; Wischhof, L.DZNE* ; Eikens, F. ; Odainic, A. ; Spitzer, J. ; Griep, A.DZNE* ; Schwartz, S. ; Bano, D.DZNE* ; Latz, E.DZNE* ; Melki, R. ; Heneka, M. T. (Last author)DZNE*

2021
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.cell.2021.09.007

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.

Keyword(s): Actins: metabolism (MeSH) ; Aged (MeSH) ; Aged, 80 and over (MeSH) ; Animals (MeSH) ; Apoptosis (MeSH) ; Cell Membrane Structures: metabolism (MeSH) ; Cytoskeleton: metabolism (MeSH) ; Down-Regulation (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Inflammation: genetics (MeSH) ; Inflammation: pathology (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism (MeSH) ; Male (MeSH) ; Mice, Inbred C57BL (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Microglia: ultrastructure (MeSH) ; Mitochondria: metabolism (MeSH) ; Nanotubes (MeSH) ; Protein Aggregates (MeSH) ; Proteolysis (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Transcriptome: genetics (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; LRRK2 ; alpha-synuclein ; cell-to-cell transfer ; clearance ; degradation ; microglia ; synucleinopathies ; tunneling nanotubes

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Contributing Institute(s):

1. Neuroinflammation, Biomarker (AG Heneka ; AG Heneka)
2. Aging and Neurodegeneration (AG Bano)
3. Interventional Trials and Biomarkers in Neurodegenerative Diseases (Biomarker)
4. Innate Immunity in Neurodegeneration (AG Latz ; AG Latz)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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