Astroglia proliferate upon biogenesis of tunneling nanotubes and clearance of α-synuclein toxicities

Abstract Astrocytic cells are a subtype of glial cells that engulf pathogenic aggregates derived from degenerative neurons to facilitate its degradation. Here, we show that exposure to α-SYN protofibrils caused a transient increase in biogenesis of tunneling nanotubes (TNTs) in primary astrocytes and astrocyte-origin cancer cell-lines (U-87 MG, U251). Biogenesis of nascent TNTs corresponds to α-SYN protofibril-induced organelle toxicities, increased reactive oxygen species (ROS), and oxidative stress-induced premature cellular senescence. These TNTs mediate cell-to-cell transfer of α-SYN protofibrils, toxic lysosomes and mitochondria. Biogenesis of TNTs precedes clearance of α-SYN-induced organelle toxicities, cellular ROS levels and reversal of cellular senescence. Consequences of cellular clearance results in enhanced cell proliferation. Further, we have shown α-SYN-induced senescence promotes transient localization of focal adhesion kinase (FAK) in the nucleus. FAK mediated regulation of Rho-associated kinases may have a role in the biogenesis of TNTs, successively proliferation. Our study emphasizes that TNT biogenesis may have a potential role in the clearance of α-SYN toxicities and reversal of stress-induced cellular senescence, consequences of which cause enhanced proliferation in the post-recovered astroglia cells. Highlights α-SYN protofibrils treated astroglia cells proliferate upon transient biogenesis of TNTs. Transient TNT biogenesis precedes clearance of α-SYN toxicities and reversal of senescence. Stress-induced senescence results in nuclear localization of FAK and ROCK mediated TNT biogenesis. The rescued cells enhance proliferation through ROCK mediated ERK1/2 and NFκB signalling cascades. Synopsis Graphical Abstract: α-SYN protofibrils-induced biogenesis of tunneling nanotubes (TNTs) aids to enhance cellular clearance of toxic burdens as a cellular survival strategy. α-SYN protofibrils treated toxic senescence cells regulate FAK mediated modulation of ROCK signalling cascades to promote TNT biogenesis and rescue the cellular toxicities. The rescued cells eventually enhance cell proliferation.