Tag Archives: Chiara Zurzolo

Structure of tunneling nanotubes (TNTs) challenges the dogma of the cell

There is a video that accompanies the news but I strongly advise reading the press release first, unless you already know a lot about cells and tunneling nanotubes.

A January 30, 2019 Institut Pasteur press release (also on EurekAlert but published Jan.31, 2019) announces the work,

Cells in our bodies have the ability to speak with one another much like humans do. This communication allows organs in our bodies to work synchronously, which in turn, enables us to perform the remarkable range of tasks we meet on a daily basis. One of this mean of communication is ‘tunneling nanotubes’ or TNTs. In an article published in Nature Communications, researchers from the Institut Pasteur leaded by Chiara Zurzolo discovered, thanks to advanced imaging techniques, that the structure of these nanotubes challenged the very concept of cell.

As their name implies, TNTs are tiny tunnels that link two (or more cells) and allow the transport of a wide variety of cargoes between them, including ions, viruses, and entire organelles. Previous research by the same team (Membrane Traf?c and Pathogenesis Unit) at the Institut Pasteur have shown that TNTs are involved in the intercellular spreading of pathogenic amyloid proteins involved in Alzheimer and Parkinson’s disease. This led researchers to propose that they serve as a major avenue for the spreading of neurodegenerative diseases in the brain and therefore represent a novel therapeutic target to stop the progression of these incurable diseases. TNTs also appear to play a major role in cancer resistance to therapy. But as scientists still know very little about TNTs and how they relate or differ from other cellular protrusions such as filopodia, they decided to pursue their research to deal with these tiny tubular connections in depth.

The dogma of cell unit questioned

A better understanding of these tiny tubular connections is therefore required as TNTs might have tremendous implications in human health and disease. Addressing this issue has been very difficult due to the fragile and transitory nature of these structures, which do not survive classical microscopic techniques. In order to overcome these obstacles, researchers combined various state-of-the-art electron microscopy approaches, and imaged TNTs at below-freezing temperatures.

Using this imaging strategy, researchers were able to decipher the structure of TNTs in high detail. Specifically, they show that most TNTs – previously shown to be single connections – are in fact made up of multiple, smaller, individual tunneling nanotubes (iTNTs). Their images also show the existence of thin wires that connect iTNTs, which could serve to increase their mechanical stability. They demonstrate the functionality of iTNTs by showing the transport of organelles using time-lapse imaging. Finally, researchers employed a type of microscopy known as ‘FIB-SEM’ to produce 3D images with sufficient resolution to clearly identify that TNTs are ‘open’ at both ends, and thus create continuity between two cells. “This discovery challenges the dogma of cells as individual units, showing that cells can open up to neighbors and exchange materials without a membrane barrier” explains Chiara Zurzolo, head of the Membrane Traf?c and Pathogenesis Unit at the Institut Pasteur.

A news step in cell-to-cell communication decoding

By applying an imaging work-flow that improves upon, and avoids, previous limitations of tools used to study the anatomy of TNTs, researchers provide the first structural description of TNTs. Importantly, they provide the absolute demonstration that these are novel cellular organelles with a defined structure, very different from known cell protrusions. “The description of the structure allows the understanding of the mechanisms involved in their formation and provides a better comprehension of their function in transferring material directly between (the cytosol of) two connected cells” says Chiara Zurzolo. Furthermore, their strategy, which preserves these delicate structures, will be useful for studying the role TNTs play in other physiological and pathological conditions

This work is an essential step toward understanding cell-to-cell communication via TNTs and lays the groundwork for investigations into their physiological functions and their role in spreading of particles linked to diseases such as viruses, bacteria, and misfolded proteins.

The researchers have kindly produced a version of the video in English,

Here’s a link to and a citation for the paper,

Correlative cryo-electron microscopy reveals the structure of TNTs in neuronal cells by Anna Sartori-Rupp, Diégo Cordero Cervantes, Anna Pepe, Karine Gousset, Elise Delage, Simon Corroyer-Dulmont, Christine Schmitt, Jacomina Krijnse-Locker & Chiara Zurzolo. Nature Communications volume 10, Article number: 342 (2019) DOI https://doi.org/10.1038/s41467-018-08178-7 Published 21 January 2019

This paper is open access.

Nanotubes tunnel between neurons in Parkinson’s disease

An Aug. 22, 2016 news item on ScienceDaily describes how scientists from the Institut Pasteur (France) have developed insight into one of the processes in Parkinson’s disease,

Scientists have demonstrated the role of lysosomal vesicles in transporting alpha-synuclein aggregates, responsible for Parkinson’s and other neurodegenerative diseases, between neurons. These proteins move from one neuron to the next in lysosomal vesicles which travel along the ‘tunneling nanotubes’ between cells.

An Aug. 22, 2016 Institut Pasteur press release (also on EurekAlert), expands on the theme,

Synucleinopathies, a group of neurodegenerative diseases including Parkinson’s disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs.

In this study, scientists from the Membrane Traffic and Pathogenesis Unit, directed by Chiara Zurzolo at the Institut Pasteur, used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons.

This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies.

These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

Here’s a link to and a citation for the paper,

Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes by Saïda Abounit, Luc Bousset, Frida Loria, Seng Zhu, Fabrice de Chaumont, Laura Pieri, Jean-Christophe Olivo-Marin, Ronald Melki, Chiara Zurzolo. The EMBO Journal (2016) e201593411 DOI 10.15252/embj.201593411 Published online 22.08.2016

This paper is behind a paywall.