Chiara Zurzolo
Membrane Traffic and Pathogenesis Unit, Department of Cell Biology and Infection, Pasteur Institute, Paris, France
Tunneling Nanotubes: Reshaping connectivity and roles in the progression of neurodegenerative diseases
Tunneling nanotubes (TNTs) are actin-based cellular connections that enable direct transfer of vesicles, organelles, and protein aggregates between cells. TNTs have been characterized in neurons, microglia, and astrocytes, where under homeostatic conditions they support intercellular organelle exchange. However, TNTs can be hijacked by pathogens and amyloid proteins involved in neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Using a connectomic approach, we identified TNT-like connections in the developing mouse cerebellum (Cordero-Cervantes et al., Science Advances, 2023), supporting the hypothesis that TNTs contribute to early neuronal network formation. This hypothesis is also supported by our recent findings showing functional TNTs in the zebrafish embryo (Korenkova et al., Dev Cell, 2025)
In adult tissue, TNTs are induced by stress and inflammation, linking them to neurodegenerative disease progression. We previously demonstrated that α-synuclein and tau aggregates spread via TNTs, providing a mechanism for pathological propagation (for review see Palese et al., Physiol Rev, 2025). In PD models, α-synuclein aggregates increase TNT formation and transfer preferentially from neurons to microglia, while microglia deliver healthy mitochondria to stressed neurons, suggesting a bidirectional exchange that may balance propagation and rescue (Chakraborty et al., Cell Death and Disease, 2023).
Using advanced live-cell imaging and human iPSC-derived neuron–microglia co-cultures, we further show that aggregate-induced mitochondrial and lysosomal dysfunction, together with impaired autophagy, drives directional intercellular transfer and alters neuron–microglia communication. These findings identify TNTs as key regulators of neuroglial crosstalk and disease progression.
In my talk, I will discuss the role of TNTs in neurodegenerative disease propagation, in the crosstalk between microglia and neurons, but I will also touch upon our studies on the molecular mechanism of TNT formation and presence in living organisms.
References
- Korenkova O, et al., Dev Cell. 2025 doi: 10.1016/j.devcel.2024.10.016.
- Palese F, et al., Physiol Rev. 2025 doi: 10.1152/physrev.00023.2024.
- Henderson JM, et al., EMBO J. 2023 doi: 10.15252/embj.2023113761.
- Chakraborty R, et al., Cell Death Dis. 2023 doi: 10.1038/s41419-023-05835-8.
- Cordero Cervantes D, et al., Sci Adv. 2023 doi: 10.1126/sciadv.adf3471.
- Chastagner P, et al., EMBO Mol Med. 2020 doi: 10.15252/emmm.202012025.