Project overview
Primary Familial Brain Calcification (PFBC) is a progressive, neurodegenerative disease characterised by deposits of calcium phosphate in the brain. PFBC is likely underdiagnosed and underestimated with predicted prevalence of 2-6 per 1000 people. Symptoms include severe movement disorders, cognitive impairment, and psychiatric disorders. Variations in seven genes expressed at the neurovascular junction are implicated in PFBC, however the mechanistic basis through which these variations cause disease remains underexplored. One of these genes encodes the carbohydrate-processing enzyme MYORG, which is highly expressed in astrocytes. Based on shared localisation and homology with enzymes involved in protein secretion, I hypothesise that MYORG has upstream regulatory roles in the export of machinery needed to maintain ion homeostasis. It is unclear if all MYORG genetic variants in patients cause its dysfunction and lead to PFBC. I will use a three-pronged strategy to understand the role of MYORG in PFBC: [1] Establish pipelines to investigate if and how genetic variations of MYORG cause enzyme dysfunction, using both recombinant protein and intracellular assays in the astrocytoma cell line U373-MG. [2] Use proximity-based labelling approaches to verify that MYORG acts as a central regulator of proteins implicated in PFBC. [3] Develop new substrates and inhibitors of MYORG to identify and explore proteome alterations caused by MYORG loss-of-function. These three approaches will generate resources and data, and develop international collaborative networks needed to pursue major research programmes to fully uncover the role and therapeutic potential of MYORG in PFBC.
