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*, Abinaya Raghavan1, Suchana Chatterjee1, Rachana Kashyap1,
1Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education – Bengaluru, India
*Presenting author
Abstract: Astrocytes play crucial neuroprotective roles by internalizing pathogenic aggregates, facilitating their degradation. We showed that tunneling nanotubes (TNTs), an emerging route of long-range intercellular communication, facilitate the clearance of α-SYN protofibrils-induced toxic burdens in primary astrocytes and astroglia cells. α-SYN protofibril-induced ROS and mitochondrial toxicities in astroglia resulted in premature senescence and transient localization of phosphorylated focal adhesion kinase (pFAK) in the nucleus, aiding in actin modulation via Rho-associated kinase and formation of transient TNTs. Further, we observe that TNT formation helps restore actin cytoskeleton tension and the integrity of nuclear Lamin A/C, reversing α-SYN-induced senescence. Using the nucleus flatness index and isometric scale factor from quantitative microscopy, we demonstrate that loss of Lamin A/C integrity is associated with reduced actin-cytoskeleton stress. Small molecules such as Cytochalasin-D, Nocodazole, and Jasplakinolide, which modulate the actin cytoskeleton, inhibit the formation of TNTs and prevent the reversal of α-SYN-induced senescence state. We have also observed that the released SASP (senescence-associated secretory phenotypes) factors from senescent astroglia are involved in cell-matrix modulation, pFAK-ROCK-mediated actin stress regulation, and TNT-biogenesis. Our study explains how TNT biogenesis and temporary nuclear translocation of pFAK lead to the modulation of actin cytoskeleton stress and Lamin A/C-mediated nuclear structural integrity, which aids in the survival of α-SYN-treated toxic cells by reversing oxidative stress-induced senescence.
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