Mapping the neuroanatomy of deregulated lipid metabolism and signaling pathways in PHARC syndrome.

Abstract

My doctoral research described in this thesis largely entails mapping deregulated lipid metabolism and signaling pathways focused around the neurological disorder, PHARC, an autosomal recessive human genetic disease. It is an age dependent neurodegenerative disease presumed to be caused by defective lysophosphatidylserine (lyso-PS) signaling arising out of disrupted lyso-PS metabolism. Lyso-PS is principally metabolized by two enzymes of serine hydrolase family – ABHD16A (biosynthetic) and ABHD12 (degradative) in the mammalian central nervous system. As a part of my doctoral research, I purified and biochemically characterized lyso-PS biosynthetic enzyme i.e. ABHD16A. I mapped the spatial metabolic route of lyso-PS in the mammalian brain and identified its crucial signaling effects in neurons and microglial cells. I have also demonstrated how defective lyso-PS signaling leads to the aberrant microglial activation (in turn neuroinflammation) through Toll like receptor 2 (TLR2) and its participation in granule neuron – Purkinje neuron communication (through phosphorylation pathways) in the cerebellum. I found that the loss of ABHD12 leads to elevated phagocytosis under immune stress possibly through oxidized phosphatidylserine accumulation and signaling. I could successfully reduce the age dependent neuroinflammation in ABHD12 knockout (KO) mice by administering minocycline and also by blocking ABHD16A activity. In short, we show that TLR2 and/or ABHD16A could be a potential therapeutic target and minocycline as one of the active small molecules for treating neuroinflammation in ABHD12 KO mice. Going ahead, it remains an interesting scientific pursuit to test if sensory motor defects of ABHD12 KO mice can be rescued by blocking ABHD16A and/or TLR2 receptor.