Regulation of Vitamin K-Dependent Protein Gas6 in the Brain and in Neurological Disease

Abstract

The vitamin K-dependent protein Gas6 is known for regulating cell survival and the immune response in various tissues, including the CNS. This suggests a beneficial role for Gas6 in controlling the progress of neurodegenerative diseases such as multiple sclerosis (MS). Gas6 is a ligand for the TAM receptor tyrosine kinases, through which it has been shown to exert anti-inflammatory and pro-repair effects in the brain. Gas6 is fully functional when it contains a series of multiple -carboxyglutamic acid (Gla) residues that have been modified in a vitamin K-dependent manner. However, the relationship between Gas6 and vitamin K have not been determined in the CNS. This study aimed to investigate the regulation of Gas6 by vitamin K in CNS cells and tissues through analysis of Gas6 composition of Gla residues. A novel immunoassay was developed to quantify specifically -carboxylated Gas6 protein (Gla-Gas6). These investigations have shown the first evidence of a functional and regulatable vitamin K cycle in human and rodent brains. Human and mouse brain cells in culture released Gas6 protein, whose Gla content could be increased or reduced by exogenous K vitamers and warfarin, respectively. Also, analysis of human brain tissue revealed that Gas6 levels were higher in inflammatory lesions of MS brains. In addition, Gas6 levels were significantly lower in cerebrospinal fluid of MS compared to non-MS subjects. These findings have therefore demonstrated an imbalance in the vitamin K dependent -carboxylation of Gas6 within the human MS brain. Furthermore, the evidence that endogenous brain Gla-Gas6 levels can be altered by exogenous vitamin K suggests its intake as a potential approach for prevention or delay of neurodegenerative diseases featuring chronic neuroinflammation. The study also proposes Gla-Gas6 as a potential novel biomarker for these diseases which warrants further investigation.

Date of Award	24 May 2023
Original language	English
Awarding Institution	University of Portsmouth
Supervisor	Sassan Hafizi (Supervisor) & Asmita Sautreau (Supervisor)