Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration

Monique A. Johnson, Yien Ming Kuo, Shawn K. Westaway, Susan M. Parker, Katherine H.L. Ching, Jane Gitschier, Susan J. Hayflick

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Mutations in the pantothenate kinase 2 gene (PANK2) lead to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). This neurodegenerative disorder is characterized by iron accumulation in the basal ganglia. Pantothenate kinase is the first enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B5). PANK2, one of four human pantothenate kinase genes, is uniquely predicted to be targeted to mitochondria. We demonstrate mitochondrial localization of PANK2 and speculate on mechanisms of secondary iron accumulation in PKAN. Furthermore, PANK2 uses an unconventional translational start codon, CUG, which is polymorphic in the general population. The variant sequence, CAG (allele frequency: 0.05), leads to skipping of the mitochondrial targeting signal and cytosolic localization of PANK2. This common variant may cause mitochondrial dysfunction and impart susceptibility to late-onset neu rodegenerative disorders with brain iron accumulation, including Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)282-298
Number of pages17
JournalAnnals of the New York Academy of Sciences
Volume1012
DOIs
StatePublished - Jan 1 2004

Keywords

  • Brain iron
  • CoA
  • Hallervorden-Spatz syndrome
  • Mitochondrial localization
  • PKAN
  • Pantothenate kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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