Role of TGF-β1 Pathway in Blood-Brain Barrier Permeability in Cerebral Adrenoleukodystrophy

Cerebral adrenoleukodystrophy (CALD) is a devastating and rapidly progressive X-linked neurological disorder. CALD is caused by mutations in the ABCD1 gene. ABCD1 encodes an ATP-binding cassette subfamily D transporter protein which is responsible for the import of very long chain fatty acids (VLCFA) into peroxisomes. Children that develop this cerebral form of adrenoleukodystrophy are unable to break down VLCFAs which cause lesions to appear, indicating blood-brain barrier (BBB) disruptions have occurred. 

The BBB is made of tightly bound endothelium cells, pericytes, and astocytic feet. The tight junction protein Claudin-5 (CLDN5) becomes leaky during BBB disruption due to ABCD1 loss of function, causing lymphocytes to enter into the brain. This is hypothesized to cause the acute progressive phase to begin after which stopping the disease becomes extremely difficult. Thus, the goal of our research is to target the small window before BBB disruption occurs to halt the disease. To do this, the TGF-β1 pathway was studied by creating an in vitro BBB model to recapitulate CALD. Upstream and downstream transcription factors, SMAD3, FOXO1, and TGF-β1 of the pathway were regulated to study their effects on the CLDN5 protein, in order to determine its role in keeping the BBB intact. Drawing on what is known about the pathology of CALD, my research focuses on furthering the understanding of the canonical pathway of the TGF-β1 pathway and how we can overcome its consequences when dysregulated. It was found that the FOXO1 transcription factor is a critical upstream candidate for the regulation of CLDN5.