The overall goal of this project is to delineate the molecular pathogenesis of a form of syndromic retinitis pigmentosa called pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder includes extrapyramidal dysfunction and iron accumulation in the basal ganglia. PKAN is caused by mutations in PANK2, one of four human genes to encode a key regulatory enzyme in coenzyme A (CoA) biosynthesis, called pantothenate kinase. Since PANK2 is uniquely associated with mitochondria, we hypothesize that defects lead to CoA deficiency, energy and lipid metabolic abnormalities, oxidative damage and apoptosis in susceptible tissues. We propose to investigate how PANK2 defects cause retinal and neuronal degeneration.
Our specific aims are: 1) to create Pank2 defective mouse mutants representing a spectrum of disease severity and delineate their associated phenotypes; 2) to identify metabolic and molecular perturbations in pantothenate kinase 2 deficiency in vivo and in vitro; and 3) to determine whether mutations in PANK2 are associated with age-related macular degeneration or idiopathic pigmentary retinopathy. Knowledge about the genetic basis of PKAN has enabled delineation of a clinically recognizable disease, as well as the development of a molecular diagnostic test and new ideas for rational therapies. This discovery has linked a previously unsuspected metabolic pathway with retinopathy and neurodegeneration and has illuminated a possible role for defects in this pathway in related, more common disorders that share pathologic features with PKAN, including age-related macular degeneration, retinitis pigmentosa and Parkinson disease.
| Hayflick, Susan J (2014) Defective pantothenate metabolism and neurodegeneration. Biochem Soc Trans 42:1063-8 |
| Williams, Sarah; Gregory, Allison; Hogarth, Penelope et al. (2013) Metabolism and energy requirements in pantothenate kinase-associated neurodegeneration. Mol Genet Metab 110:336-41 |
| Gregory, Allison; Hayflick, Susan J (2011) Genetics of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep 11:254-61 |
| Polster, Brenda J; Yoon, Moon Y; Hayflick, Susan J (2010) Characterization of the human PANK2 promoter. Gene 465:53-60 |
| Kruer, Michael C; Paisán-Ruiz, Coro; Boddaert, Nathalie et al. (2010) Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 68:611-8 |
| Polster, Brenda; Crosier, Moira; Lindsay, Susan et al. (2010) Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy. Brain Res Bull 83:374-9 |
| Polster, Brenda J; Westaway, Shawn K; Nguyen, Thuy M et al. (2010) Discordant expression of miR-103/7 and pantothenate kinase host genes in mouse. Mol Genet Metab 101:292-5 |
| Gregory, A; Polster, B J; Hayflick, S J (2009) Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 46:73-80 |
| McNeill, A; Birchall, D; Hayflick, S J et al. (2008) T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 70:1614-9 |
| Gregory, A; Westaway, S K; Holm, I E et al. (2008) Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71:1402-9 |
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