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.
