20 research outputs found
The restorative role of annexin A1 at the blood–brain barrier
Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune
system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the
study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the
peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule
in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective
actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the
possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS
vasculature, and its potential for repairing blood–brain barrier damage in disease and aging
Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2
Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploited a new method, differential viral accessibility (DIVA), to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common alteration affecting the ATPase domain in CMT patients (p.Arg252Trp) hyperactivates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease