Can carbon nanotube scrutinize intimate tissue organizations? Uncovering early dys-organization of the brain extracellular space in Parkinson disease – nanoSPACE

Most types of cell communication in the brain require the transfer of molecules through the extracellular space (ECS). A correct transfer of molecules within the ECS is thus essential to convey both local and long-distance communication. Although ECS is often considered as a static space with foam of molecules, it emerged that components of the extracellular matrix specifically contribute to intercellular communication in the brain. Interestingly, seminal recent discoveries have grounded the hypothesis that neurodegenerative diseases (e.g. Parkinson and Alzheimer) relies on a cell-to-cell prion transfer of misfolded proteins as well as the accumulation of such proteins in the ECS. Clearing of such proteins by changes in the volume of ECS has even been recently suggested as a physiological mechanism, shedding light upon the need for understanding its actual morphology and rheology changes in a pathological context. This would indeed have many implications in the neurodegenerative disease comprehension, early diagnostic and eventually drug development strategy.

However, understanding this central compartment has surprisingly been largely ignored, both in the healthy and neurodegenerative brains and it thus represents a knowledge frontier. This ignorance has mainly conceptual and methodological roots, i.e. the static representation of brain tissue and the current lack of dedicated relevant investigation tools. .

In this high-risk project, we will develop the tools to intimately explore the ECS, the last “terra incognita” of the brain. Breakthroughs in single molecule imaging dedicated to the study of the brain tissue in different functional states will be required. Based on our unique individual and common expertise, our pioneering main objectives can be enounced as follows:
- during the pilot phase of the project, we will establish that luminescent single wall carbon nanotubes (SWCNTs) can act as unique near infrared nano-emitters capable of probing the ECS local environment in living cerebral tissues. To this aim, we will design and combine novel imaging modalities based on SWCNT imaging and 3D diffractive tomography, and use several model systems for fully quantitative biophysical investigations.
- during the second phase of the project, we will apply these innovative tools to explore and unravel the early disorganization of the brain ECS in Parkinson’s disease. In particular, we will study the ECS remodeling along the pathology propagation in ground-breaking animal model of Parkinson’s disease we recently validated, deciphering the relationship between ECS spatio-temporal organization, neuronal communication and the neuronal dysfunction, and establishing the proof-of-principle that such innovative tool can be used to diagnose early alteration.

The strength of this highly multidisciplinary project relies on an exceptional complementary group formed by 3PIs with unique and world expertise in nano-biophotonics, neurophysiology and neurodegenerative diseases: Cognet (LP2N - Institut d’Optique, CNRS & Univ. Bordeaux), Groc (IINS - CNRS & Univ. Bordeaux) and Bezard (IMN- CNRS &Univ. Bordeaux). Each PI is a world leader in his field with a strong culture for interdisciplinarity, as evidenced by previous fruitful collaborations. Cognet-Groc (8 joint publications ~ 800 citations) and Groc-Bezard (3 joint recent publications), have already established tight collaborations, although this is the first time that the 3 expertises will be integrated in a common project.

More generally, we believe that the expected findings of this project should go largely beyond the sole impact on the Parkinson disease. Indeed, it is known that ECS modifications also occur in other pathological disorders than Parkinson’s disease and also during neuronal communication, learning and aging where constant remodeling takes place. Our new methodologies should also be immediately transferable to other organ investigation (e.g. tumor development in oncology).