alpha-Synuclein triggers intercellular nanotubes formation to prevent apoptosis in astroglia by promoting stemness

06/07/202625/07/2026

AI Summary

α-Synuclein protofibrils induce actin remodelling and pFAK nuclear translocation, triggering tunnelling nanotube formation in astroglia.
Nuclear pFAK co-localises with Nanog, promoting Mdm2-mediated p53 ubiquitination and increased autophagy, thereby enhancing stemness and apoptosis resistance.
Tunnelling nanotubes transiently transfer mitochondria between astroglia, supporting metabolic stability; inhibiting TNTs or Nanog prevents p53 degradation and cell rescue.

AI Summary

Recent studies indicate that α-Synuclein (α-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.

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 α-SYN protofibrils.

This study reveals that the TNT formation pathway promotes pFAK-Nanog interaction in the nucleus, leading to p53 degradation, which protects astroglia against α-SYN proteotoxicity and prevents apoptosis.

Basic summary

Cell Biosci. 2026 Jul 5. doi: 10.1186/s13578-026-01617-9. Online ahead of print.

ABSTRACT

Astrocytes play a significant role in neuroprotection by internalizing neurodegenerative aggregates and facilitating their degradation. Recent studies indicate that α-Synuclein (α-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 α-SYN protofibrils induce aberrant mitochondria with decreased membrane potential (Ψm) 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 α-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 α-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 α-SYN proteotoxicity and prevents apoptosis.

PMID:42402587 | DOI:10.1186/s13578-026-01617-9

Document this CPD