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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1.      Hayflick SJ, Westaway SK, Levinson B,  Zhou B, Johnson MA,  Ching KHL, Gitschier J. Genetic, clinical and radiographic delineation of Hallervorden Spatz syndrome. New England Journal of Medicine 2003 348(1):33-40

2.      Johnson MA, Kuo YM Westaway SK, Parker SM, Gitschier J, Hayflick SJ. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Annals of the New York Academy of Sciences. 2004 1012:282-298

3.      Egan RA, Weleber RG, Hogarth P, Gregory A, Coryell J, Westaway SK, Das S, Gitschier J and Hayflick SJ. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). American Journal of Ophthalmology. 2005 140(2):267-74.

4.      Hayflick SJ, Hartman M, Coryell J, Gitschier J, and Rowley H. Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. American Journal of Neuroradiology. 2006 27(6):1230-3

5.      Morgan NV, Westaway SK, Morton JEV, Gregory A, Gissen P, Sonek S, Cangul H, Coryell JC, 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. The calcium-independent phospholipase A₂ gene, PLA2G6, is mutated in a spectrum of childhood neurodegenerative disorders with high brain iron.  Nature Genetics. 2006 38(7), 752-4.

6.      Kuo YM,  Hayflick SJ, Gitschier J. Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration. Journal of Inherited Metabolic Disease. 2007 30(3):310-7

7.      Gregory A, Westaway SK,  Holm IE, Kotzbauer PT, Hogarth P, Sonek S, Coryell JC, Nguyen TM, Nardocci N, Zorzi G, Todriguez D, Desguerre I, Bertini E, Simonati A, Levinson B, Dias C, Barbot C, Carrilho I, Santos M, Malik I, Gitschier J and  Hayflick SJ. Neurodegeneration associated with genetic defects in phospholipase A₂. Neurology 2008  In Press

8.      Gregory A, Polster B and Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. Journal of Medical Genetics 2008  In Press

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