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

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 a-synuclein (a-syn) fibrils and their clearance. We found that microglia exposed to a-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer a-syn from overloaded microglia to neighboring naive microglia where the a-syn cargo got rapidly and effectively degraded. Lowering the a-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 a-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 a-syn clearance. ll

Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds

“…Microglia were juxtaposed to nerve cells with α-synuclein inclusions. Unlike what has been reported previously [ 65 , 66 ], we failed to observe α-synuclein- or pFTAA-positive inclusions in microglia. Nerve cells labelled by pFTAA were also pS129 α-synuclein-positive.…”

Intercellular Communication in the Brain through Tunneling Nanotubes

“…In particular, TNTs have been found in vitro to convey fibrillar α-synuclein (α-syn) cargoes from α-syn –overloaded astrocytes to microglia where it is degraded. Similarly, it was recently reported that α-syn-overloaded microglia have the capacity to form TNTs, as observed both in vitro and in vivo, allowing them to discharge their excessive α-syn aggregate contents to neighboring naive microglia, which take care of their clearance [ 117 ]. Beyond their role in α-syn degradation, the TNTs that connect naive microglia to affected microglia have also been shown to mediate the transfer of mitochondria to these affected microglia, thereby preventing cell death and inflammation [ 117 ].…”

“…Similarly, it was recently reported that α-syn-overloaded microglia have the capacity to form TNTs, as observed both in vitro and in vivo, allowing them to discharge their excessive α-syn aggregate contents to neighboring naive microglia, which take care of their clearance [ 117 ]. Beyond their role in α-syn degradation, the TNTs that connect naive microglia to affected microglia have also been shown to mediate the transfer of mitochondria to these affected microglia, thereby preventing cell death and inflammation [ 117 ]. Finally, TNT-mediated transfer of misfolded protein aggregates between neurons has been documented in vitro in several studies [ 59 , 74 , 75 ].…”

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

“…The study suggests that transfer of mitochondria from healthy cells via TNTs reverses the cellular stress in early stage of apoptosis. A recent work [ 112 ] has shown that α-synuclein protofibril-induced defects in cellular degradation machineries in microglia enhance cell to cell networks via TNTs to transfer the burden of proteotoxic aggregates to neighbouring cells. The study has also shown that mitochondrial shuffling and sharing of proteotoxic burdens via TNTs alleviate ROS levels and rescue cells from ROS-induced apoptosis.…”

“…Recently, another study has reported that Arp2/3 negatively regulates biogenesis of TNTs in CAD cells [ 5 ]. Another recent study [ 112 ] has shown that inhibition of ROCK (using chemical inhibitor Y-27632), a downstream signalling molecule of Rho/Rac/Cdc42, promotes biogenesis of TNTs. The study has indicated that ROCK inhibition promotes TNT formation via Myosin II regulated f-actin modulation.…”