Jul 11

Brain extracellular microenvironment and Parkinson's disease

An intriguing interplay between the extracellular space, matrix and glia

In a new study published in Nature Communications by Dr. Federico N. Soria and other colleagues have been able to "illuminate" the extracellular compartment of parkinsonian mice, revealing its structure and diffusion at an unprecedented scale.

Hereby, they obtained precious information about this dark side of the brain, for the first time in pathological conditions. This examination at "super-resolution" allowed the researchers to discover local alterations in the extracellular space of the parkinsonian brain, modify them, and protect partially the neurons that are normally lost in this pathology. Moreover, the study describes an intriguing relation between the hyaluronan matrix (main component of the neural matrix) and microglia (the chief immune cell in the brain). In particular, how these cells remodel the extracellular matrix by phagocytosis, reducing it in an animal model of Parkinson's disease. This, in turn, exacerbates further activation of microglia, creating a positive feedback loop.

Synucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling

The brain extracellular microenvironment, described 50 years ago, surrounds every cell of the central nervous system. It is composed of a dynamic compartment, the extracellular space, which contains the interstitial fluid and a gel-like scaffold known as the extracellular matrix. This matrix is a dense network of macromolecules whose structural framework resides in the sugar polymer hyaluronan (also known as Hyaluronic Acid). The primary role of the matrix is to provide adhesion support for cells, but its role goes well beyond: through its structure and physico-chemical properties, the matrix is involved in key cellular functions such as synaptic plasticity or response to injury. The matrix has been widely studied in pathologies such as cancer or brain ischemia; however, little is known about its involvement in the pathophysiology of neurodegenerative diseases such as Parkinson's.

Since Santiago Ramón y Cajal's description of a neuron more than 100 years ago, microscopy has played a critical role in understanding the organization and function of the brain. Recent super-resolution fluorescence microscopy offers up to tenfold improvement in resolution compared to classical optical microscopy and allows scientists to visualize the inner workings of cells and biomolecules at unprecedented image definition.

As Dr. Soria told us "Using state-of-the-art technologies developed in Bordeaux by the teams of Laurent Cognet and Laurent Groc and Erwan Bezard –where I carried out my postdoctoral endeavor– we were able to visualize the precise organization of the extracellular space in a model of Parkinson's disease".

Dr. Federico N. Soria is an Spaniard of Argentine origin. He is the first author of this work imagined and coordinated by Cognet and Bezard. "This may be the key to understand how proteins such as alpha-synuclein transfer between cells of the brain and periphery", added Dr. Bezard, director of a Bordeaux-based world-renowned laboratory specialized in Parkinson's disease and synucleinopathies."Moreover, the possibility to explore nanoscale organization of the extracellular microenvironment will open new avenues to further understand brain physiology in health and disease".