Scientists at the Institut Pasteur have identified the mechanism that triggers the formation of nanotubes between neurons and immune cells in the brain. Nanotubes enable communication and transfer of toxic proteins and damaged cellular components involved in Parkinson's disease and other neurodegenerative conditions – a discovery that opens up new therapeutic prospects.
The team led by Chiara Zurzolo in the Membrane Traffic and Pathogenesis Unit at the Institut Pasteur recently published a study in Nature Communications that sheds new light on the mechanisms that enable Parkinson's disease to spread in the brain. The focus of the research was synucleinopathies, a group of neurodegenerative diseases (also including Lewy body dementia) characterized by the abnormal accumulation of the alpha-synuclein protein (α-Syn) in the brain.
Tunnels between brain cells
The team has played a pioneering role in research on the intercellular connections known as tunneling nanotubes (TNTs), revealing their involvement in the spread of pathogenic proteins back in 2009. In 2023, the scientists showed that thin membrane bridges linking cells enabled diseased neurons to transfer their toxic α-Syn aggregates to microglia, immune cells in the brain. While this identified a functional connection between these two cell types, the underlying mechanism remained unknown.
Why and how do nanotubes form?
The latest study provides an answer. α-Syn aggregates damage mitochondria, the cell's "powerhouse." This damage leads to the release of mitochondrial DNA in the cell, which activates a defense pathway in innate immunity known as the cGAS–STING pathway.
Activation of this pathway has two major consequences:
- it remodels the actin cytoskeleton, the cell's internal scaffolding;
- it stimulates the formation of TNTs; which then serve as a conduit for transfer of toxic aggregates and damaged cellular components from neurons to microglia.
The scientists also showed that neurons transfer damaged mitochondria to microglia, where they are eliminated, and that this communication contributes to inflammatory responses in microglia.
Drivers of disease, not just symptoms
These findings change our understanding of Parkinson's disease, suggesting that mitochondrial damage and inflammation are not just consequences of disease but may actively contribute to disease progression. Membrane nanotubes also emerge as central players in this cellular communication. While they can contribute to the elimination of damaged cell components, they may also promote the spread of toxic aggregates and inflammatory signals in the brain. Developing a better understanding of these mechanisms and learning how to modulate them could pave the way for new therapeutic strategies to slow the progression of synucleinopathies.
This study continues the remarkable work of the team, which has played a pioneering role in the TNT field. After being among the first to demonstrate the involvement of TNTs in pathogenic protein spreading in 2009, the scientists achieved another important milestone in 2025 by providing the first direct visualization of nanotubes in a living organism – the zebrafish – using fluorescence microscopy. Although TNTs had been known in vitro since 2004, this breakthrough confirmed their existence and function in vivo.
Source: α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron–microglia communication, Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio & Chiara Zurzolo, Nature Communications, May 15, 2026.
