Toward an understanding of the brain interstitial system and the extracellular proteome in health and autism spectrum disorders

Introduction

Since the ancient Egyptians, the fluid in the brain has been considered a product of spirits, a pathological signature, or inert liquid. Even at the turn of the 19th century, when the cerebrospinal fluid (CSF) was first described as a physiological substance, the CSF and the interstitial fluid (ISF), the fluid surrounding all the cells of the brain, were considered solely as a cushion.

Recent Discoveries

Only more recently have studies begun to show that the compositions of these fluids can have a marked impact on brain development and animal behaviour. A number of studies have employed omics to demonstrate that the ISF and the CSF are rich in secreted proteins, RNAs, and metabolites. However, it is still unclear how these factors influence the development and function of the brain.

Research Objectives

Here, we will take a systematic approach to advance our knowledge about the role of extracellular proteins in the brain in health and disease. Using know-how in studying the causes of autism spectrum disorders (ASDs), my lab will study the effects of changes in the composition of the extracellular space of the brain at unprecedented resolution and scale. Specifically, we aim to:

1. Functionally identify proteins of the extracellular space that modulate neural development.
2. Study proteins that are packaged into extracellular vesicles and whose mutations are considered high ASD-risk factors.
3. Analyse in vivo the function of HNRNP U, an RNA-binding protein, which we identified in brain extracellular vesicles and whose mutations are tightly linked to neurodevelopmental disorders.

Significance of the Study

This endeavour will represent an important step toward a better understanding of the role of extracellular factors in brain development and function. My work will highlight an entire class of protein-encoding genes that crucially contribute to neural development by a previously underappreciated pathway, i.e., through the extracellular parenchyma, and that when altered lead to forms of ASDs which may be more amenable to treatment.