Biology subjects

Padavattan, S.

Publications and source records attributed to Padavattan, S..

4 recordsLinked to original sources

bioRxiv2026

α-Synuclein Triggers Intercellular Nanotubes Formation to Prevent Apoptosis in Astroglia by Promoting Stemness

Astrocytes play a significant role in neuroprotection by internalizing neurodegenerative aggregates and facilitating their degradation. Recent studies indicate that -Synuclein (-SYN) protofibrils promote the transfer of pathogenic aggregates and dysfunctional mitochondria between astroglia via tunneling nanotubes (TNTs), which enhances cell survival and resistance to apoptosis. However, the underlying mechanism of TNT-driven apoptosis resistance remains unclear. We find that -SYN protofibrils induce aberrant mitochondria with decreased membrane potential ({Psi}m) and promote dynamic actin remodeling by relocating phosphorylated focal adhesion kinase (pFAK) to the nucleus, which triggers TNT formation in human astrocytoma cell lines and primary murine astrocytes. The important novel finding of this study is that pFAK in the nucleus co-localizes with Nanog, a crucial transcription factor for preserving stemness, and the interaction between pFAK and Nanog is critical for promoting p53 degradation via Mdm2-mediated ubiquitination and upregulating autophagy, thereby supporting the survival of astroglia exposed to toxic -SYN protofibrils. ROCK inhibitor y-27632 also drives TNT-formation via pFAK translocation to the nucleus, colocalizes with Nanog, and enhances stemness-related gene expression. Inhibiting TNT with the actin depolymerizing agent cytochalasin-D prevents pFAK co-localization with Nanog in the nucleus and fails to protect cells from -SYN-induced apoptosis. Nanog knockdown does not degrade p53 and hinders cell rescue from apoptosis. Furthermore, these transient TNTs transfer mitochondria to adjacent cells, potentially helping maintain metabolic stability. This study reveals that the TNT formation pathway promotes pFAK-Nanog interaction in the nucleus, leading to p53 degradation, which protects astroglia against -SYN proteotoxicity and prevents apoptosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/727344v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@18d8675org.highwire.dtl.DTLVardef@76a383org.highwire.dtl.DTLVardef@e92202org.highwire.dtl.DTLVardef@1b7ee4b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Mechanical Signaling Drives Tunneling Nanotubes to Preserve Cytoskeleton Tension and Lamin Integrity Against α-Synuclein-Induced Senescence in Astroglia

Astroglia can counteract the harmful effects of -synuclein (-SYN) protofibrils and reverse premature cellular senescence by promoting tunneling nanotubes (TNTs). However, the mechanism behind this recovery is unknown. This study is the first to examine TNT-mediated mechanical stability in senescent astroglial recovery. We demonstrate that disruption of Lamin A/C in -SYN-protofibrils-treated senescent cells reduces actin-cytoskeleton stress, as measured by nucleus flatness index and isometric scale factor from quantitative microscopy. ROCK (Rho-associated kinase) inhibition, which is crucial for reducing actin-cytoskeleton tension, promotes TNTs. Small molecules like Cytochalasin-D, Nocodazole, and Jasplakinolide, which inhibit TNTs by altering actin tension other than ROCK pathway, cannot reverse senescence. RNA-sequence heatmaps reveal changes in senescence-, integrin-, and ROCK-pathway genes; STRING links these to the Hippo pathway. Experimental results show that cytosolic YAP translocation, a key regulator of Hippo pathway, is vital for TNT formation and actin-based stability in U87-MG astrocytoma and primary astrocytes. Interestingly, TNTs form between two cells with different actin tensions: one exhibits low actin tension with Hippo signaling on, while the other has higher actin tension with Hippo signaling off. The most notable observation is the high abundance of YAP inside the TNTs, along with actin. The study shows that TNTs maintain mechanical stability through Lamin A/C integrity and actin tension in -SYN-induced senescent astroglia, thereby protecting the cells, reversing senescence. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/711517v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@192307dorg.highwire.dtl.DTLVardef@ad8b75org.highwire.dtl.DTLVardef@19ece78org.highwire.dtl.DTLVardef@1056395_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Structural and functional insights into nuclear role of Parkinson's Disease-associated α-Synuclein

-Synuclein (Syn) plays a critical role in the pathogenesis of Synucleinopathies. Although increased nuclear Syn localization induces neurotoxicity, its definitive physiological role remains elusive. Previous studies on nuclear Syn are limited to its interactions with individual histones and dsDNA, leaving a significant gap in understanding its interactions with assembled histone H2a-H2b dimer and (H3-H4)2 tetramer, as well as its role in chromatin regulation. Here, we demonstrated that Syn binds specifically to both H2a-H2b and (H3-H4)2 with high affinity. Truncation studies revealed that Syn(1-103) region interacts with (H3-H4)2, while the acidic (121-140) C-terminal end is crucial for H2a-H2b binding. Sequence analysis suggests Syn-dimer binding region contains a conserved DEF/YxP motif present in other dimer-binding histone chaperones. High-resolution structure of Syn- dimer binding region with H2a-H2b complex reveals that Syn adopts two binding modes (BM1 and BM2). In BM-1, Syn utilizes nucleosomal DNA-binding surface, while in BM-2, it engages with both DNA- and the H3-interaction interface. Additionally, dimer recognition by Syn overlaps with other dimer-binding histone chaperones, suggesting Syns potential role in the nucleosome assembly/disassembly process.

biophysics↗

bioRxiv2023

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

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 -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 -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 -SYN protofibrils, toxic lysosomes and mitochondria. Biogenesis of TNTs precedes clearance of -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 -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 -SYN toxicities and reversal of stress-induced cellular senescence, consequences of which cause enhanced proliferation in the post-recovered astroglia cells. HighlightsO_LI-SYN protofibrils treated astroglia cells proliferate upon transient biogenesis of TNTs. C_LIO_LITransient TNT biogenesis precedes clearance of -SYN toxicities and reversal of senescence. C_LIO_LIStress-induced senescence results in nuclear localization of FAK and ROCK mediated TNT biogenesis. C_LIO_LIThe rescued cells enhance proliferation through ROCK mediated ERK1/2 and NF{kappa}B signalling cascades. C_LI Synopsis O_FIG O_LINKSMALLFIG WIDTH=167 HEIGHT=200 SRC="FIGDIR/small/554645v1_figa1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@9dc5bcorg.highwire.dtl.DTLVardef@20e924org.highwire.dtl.DTLVardef@aa7920org.highwire.dtl.DTLVardef@1f6274b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO -SYN protofibrils-induced biogenesis of tunneling nanotubes (TNTs) aids to enhance cellular clearance of toxic burdens as a cellular survival strategy. -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. C_FIG

cell biology↗