Brain iron accumulates in many human neurodegenerative disorders, including Parkinson disease, Alzheimer disease and HIV encephalopathy. To investigate brain iron dyshomeostasis, we study a group of rare, single gene disorders, called Neurodegeneration with Brain Iron Accumulation (NBIA). Our NBIA research has identified the first two major genes for this disorder: PANK2, which encodes a key regulatory enzyme in the biosynthesis of coenzyme A, and PLA2G6, which encodes a phospholipase A₂. Both are critical in maintaining membrane integrity. Our studies of PANK2 and its protein product currently focus on cellular localization, processing and distribution in both wild type and mutant tissue. We are exploring the genetic and biochemical perturbations in this forn of NBIA, called pantothenate kinase-associated neurodegeneration (PKAN), investigating the mechanism by which this enzymatic defect leads to high brain iron and other phenotypic features, delineating the range of humanneurologic disease associated with this pathway, and developing rational therapies, based on the gene discovery. Similar studies are underway on PLA2G6, identified in 2006 as the causative gene for Infantile Neuroaxonal Dystrophy (INAD).  Murine KO models of both disorders have been developed to serve as a resource for genetic, biochemical, radiographic, electrophysiological, and clinical studies. We collaborate with labs both at OHSU and other academic institutions, including UCSF, Stanford and the University of Birmingham. 

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Morgan NV, Westaway SK, Morton JEV, Gregory A, Gissen P, Sonek S, Cangul H, Coryell C, Canham , Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath RC, Simonati A, Schanen C, Johnson CA, Levinson B, Woods CG, Wilmot B, Kramer P, Gitschier J, Maher ER, and Hayflick SJ. _he calcium-independent phospholipase A2 gene, _LA2G6_ is mutated in a spectrum of childhood neurodegenerative disorders with high brain iron. 2006. Nature Genetics. 38(7), 752-4.

Kuo YM, Duncan JL, Westaway SK, Yang H, Nune G, Xu EY, Hayflick SJ, Gitschier J.  Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia.  Hum Mol Genet. 2005 Jan 1;14(1):49-57. Epub2004 Nov 3.

Johnson MA, Kuo YM, Westaway SK, Parker SM, Ching KH, Gitschier J, Hayflick SJ. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration.  Ann N Y Acad Sci.2004 Mar;1012:282-98.

Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KHL, Gitschier J (2003). Genetic, clinical and radiographic delineation of Hallervorden Spatz syndrome. N Engl J Med348(1):33-40.

Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ (2001). A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet8(4):345-9.

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