Kambaru, A. | Search bioRxiv

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↗

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↗