Mutations in the PLA2G6 gene cause young onset neurodegenerative disorders classified as either infantile neuroaxonal dystrophy (INAD) or neurodegeneration with brain iron accumulation (NBIA). These two disorders with overlapping features involve progressive impairment of movement, speech and cognition. The PLA2G6 gene encodes group VIA calcium-independent phospholipase A2 (Pla2g6). Our previous studies indicate that human Pla2g6 hydrolyzes both phospholipids and lysophospholipids to produce free fatty acids, and that disease-associated mutations dramatically impair the catalytic activity of the protein. This predicts two potential pathological pathways in INAD/NBIA: accumulation of Pla2g6 substrates (phospholipids) and deficiency of Pla2g6 products (free fatty acids). Previous studies in cell lines also support a role for Pla2g6 in phospholipid and fatty acid homeostasis. Accumulation of Pla2g6 substrates explains a characteristic feature of the human disease - accumulation of membranes in pathological structures termed neuroaxonal spheroids. Our previously reported Pla2g6-KO mouse model recapitulates neuroaxonal spheroid formation as well as progressive neurological impairment of the human disorder. We will use Pla2g6-KO mice to test a therapeutic approach to increase the rate of fatty acid synthesis and uptake in order to compensate for impaired release of fatty acids caused by Pla2g6 mutations. This approach will utilize a small molecule liver X receptor (LXR) agonist. LXR's are nuclear receptor transcriptional activators of sterol regulatory element binding protein 1c (SREBP-1c) expression and also directly activate the expression of proteins involved in fatty acid synthesis and uptake. The LXR agonist will be administered to Pla2g6-KO and wildtype mice. The effect of the LXR agonist on lipogenic gene expression, fatty acid synthesis, and fatty acid uptake in brain tissue will be evaluated. The effect of the LXR agonist on progressive neurological impairment will be evaluated using the rotarod test and other behavioral tests of sensorimotor function, and by histopathological analysis of brain tissue. Positive results in these studies could be translated into new therapeutic approaches in humans by utilizing LXR agonists which are currently being developed for potential therapeutic effects in regulating lipid metabolism in other disorders.
This project will test a novel therapeutic approach in a mouse model for a human neurodegenerative disorder caused by mutations in the PLA2G6 gene. Results from these studies will improve the understanding of disease mechanisms and guide the development of treatments for the human disorders known as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.