Neurodegeneration associated with brain iron accu ulation (N BIA) comprises a heterogeneous group of disorders, such as infantile neuroaxoal dystroph (INAD), in which disruption of cellular mechanisms leads to accumulation of iron in the b sal ganglia. This group includes patients with discovered mutations in the PLA2G6 gene that enc des group VI Ca '-independent phospholipase A, (iPLA2 or iPLA2P). Recently, more and more patien with INAD were identified containing mutations in the PLA2G6 gene, designated as PLA2G6-asso iated Neurodegeneration (PLAN). Our broad longterm goal is to characterize the molecular and ceHu ar mechanisms by which dysfunction of iPLA2 leads to neurodegeneration associated with brain iron accumulation in PLAN. iPLA2 catalyzes hydrolysis of sn-2 acyl chains from phospholipids a d plays an important role in cell membrane homeostasis and trafficking. Recently it was report d that iPLA2-knockout mice recapitulate the neurodegenerative features of human INAD. Little i known about how alteration of iPLA2 function causes brain iron accumulation. Previously we rep rted that inhibition of iPLA2 results in the increase of cell-membranous phosphatidylcholines containin polyunsaturated fatty acid residues that induces phosphorylation of p53 through activation of ataxia- elangiectasia mutated and Rad3-related (ATR). We have identified that hepcidin, a hormone regula ing iron export, is activated by inhibition of iPL~ in a p53 dependent manner. These findings allow u to hypothesize that dysfunction of iPLA, leads to a p53-mediated induction of hepcidin expression, ich in turn causes degradation of iron exporter ferroportin, ablation of the iron cellular export, and i on accumulation in the brain of NIBA. In this twoyear ARRA award , our objectives are: 1) to determine the expression of hepcidin in the brains of iPLA2-KO mice using in situ hybridization, 2) to det rmine the effects of mutants of iPLA2 on hepcidin expression in primary iPLA2 -I- neural cells, 3) to ch racterize p53-dependent transcriptional expression of hepcidin in the primary iPLA2 -1- neural cells, and 4) to examine the expression of hepcidin, ferroportin , and ferritin in the brain sectio s of iPLApound'-/p53-'- mice. Achieving this proposal's goals will explain why dysfunction of iPLA2 causes i on accumulation in iPLArKO mice and in INAD patients. In addition, the ARRA funding for this proj ct will preseve jobs, which will significantly contribute to the improvement of our local economy.
NIH ExPorter
NIH ExPorter