Abstract
AbstractAstrocytic 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.Highlightsα-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.SynopsisGraphical 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.
Publisher
Cold Spring Harbor Laboratory