Elucidating the novel mechanism of Blood Brain Barrier permeability regulation by the cellular iron homeostasis

The purpose of Dr. Rand’s visit in Prof.

Samira Lakhal-Littleton’s lab is to study iron homeostasis methodologies from a world-class specialists in the field and apply it to the Blood brain barrier. Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions.

In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete.

Recent evidence implicating key proteins involved in the pathogenesis of neurodegenerative conditions in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis.

A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain.

Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs may provide important insights into the maintenance of iron homeostasis within the brain.

The Blood-brain barrier (BBB) is composed of a network of vessels that form a structural and chemical barrier between the brain and systemic circulation.

Vessels of the BBB are composed of specialized endothelial cells that have extensive tight junctions that severely restrict cell permeability.

Limited permeability restricts movement of substances from the systemic circulation to the brain which buffers the brain from rapid changes in ionic or metabolic conditions.

Limited BBB permeability also protects the brain from exposure to molecules that are harmless to peripheral organs but toxic to neurons in the brain.

However, under certain conditions such as inflammation, traumatic brain injury, ischemic stroke and neurodegenerative conditions the BBB is compromised allowing for the passage of larger and hydrophilic substances.

We have recently discovered in our lab that iron metabolism directly regulates BBB permeability and we have begun elucidating the specific iron-modulating proteins responsible for this phenomenon, yet we are lacking the methodology, background and assays to fully understand and uncover the molecular events leading to this phenotype.

Prof.

Samira Lakhal-Littleton’s research centres on the study of the mechanisms governing local iron in various physiological systems and the importance of such control for normal physiological function.

Her lab discovered regulated iron export in cardiovascular cells and demonstrated its importance for normal cardiac and vascular functions (Lakhal-Littleton et al, PNAS 2015, eLife 2016, PNAS 2019). Our goal in this collaboration is to set up our in vitro BBB model in Prof.

Lakhal-Littleton’s lab in order to identify the precise molecular mechanisms linking iron homeostasis with BBB permeability.

The collaboration will involve a series of experiments in which the size of the labile iron pool within cells of the BBB is manipulated in a controlled manner, either through increased iron uptake or decreased iron release.

Prof Lakhal-Littleton’s lab has the expertise to run these types of experiments, and to obtain precise measurements of the cells’ iron status.

This study is of immense importance in helping us to identify the molecular mechanisms underlying BBB iron regulated function.