Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

Author:

Bussi Claudio1ORCID,Peralta Ramos Javier M.1,Arroyo Daniela S.1,Gallea Jose I.2,Ronchi Paolo3,Kolovou Androniki3,Wang Ji M.4,Florey Oliver5,Celej Maria S.2,Schwab Yannick36,Ktistakis Nicholas T.5,Iribarren Pablo1ORCID

Affiliation:

1. Center for Research in Clinical Biochemistry and Immunology (CIBICI-CONICET), Córdoba, Argentina

2. Center for Research in Chemical Biology (CIQUIBIC-CONICET), Córdoba, Argentina

3. EMBL, Electron Microscopy Core Facility, Heidelberg, Germany

4. Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA

5. Babraham Institute, Signalling Programme, Cambridge, UK

6. EMBL, Cell Biology and Biophysics Unit, Heidelberg, Germany

Abstract

Autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, but the exact mechanisms and causal connections are not clear and most work was done in neurons and not in microglial cells. Here we report that exogenous fibrillar but not monomeric alpha-synuclein (AS) induces autophagy in microglial cells. We extensively studied the dynamics of this response by both live-cell imaging and correlative light-electron microscopy (CLEM) and found that it correlates with lysosomal damage and is characterised by the recruitment of the selective autophagy-associated proteins TANK-binding kinase 1 (TBK1) and Optineurin (OPTN) to ubiquitinated lysosomes. In addition, we observed that LC3 recruitment to damaged lysosomes was dependent on TBK1 activity. In these fibrillar AS-treated cells, autophagy inhibition impairs mitochondrial function and leads to microglial cell death. Our results suggest that microglial autophagy is induced in response to lysosomal damage caused by persistent accumulation of AS fibrils. Importantly, triggering of the autophagic response appears to be an attempt at lysosomal quality control and not for engulfment of fibrillar AS.

Funder

Fondo para la Investigación Científica y Tecnológica

Consejo Nacional de Investigaciones Científicas y Técnicas

Secretaria de Ciencia y Tecnología - Universidad Nacional de Córdoba

Publisher

The Company of Biologists

Subject

Cell Biology

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