QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 19, 2005, 25(3):689-698; doi:10.1523/JNEUROSCI.4265-04.2005

This Article Full Text Full Text (PDF) An addendum has been published Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Kotzbauer, P. T. Articles by Lee, V. M.-Y. Search for Related Content PubMed PubMed Citation Articles by Kotzbauer, P. T. Articles by Lee, V. M.-Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Genetics Home Reference

 Previous Article  |  Next Article 

Neurobiology of Disease
Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Paul T. Kotzbauer,^1,2 Adam C. Truax,² John Q. Trojanowski,^2,3 and Virginia M.-Y. Lee^2,3

¹Department of Neurology, ²Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and ³Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5' start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.

Key words: pantothenate kinase; neurodegenerative disease; synucleinopathy; lipid metabolism; mitochondria; mitochondrial processing peptidase

---

Received Oct 13, 2004; revised November 24, 2004; accepted November 29, 2004.

This article has been cited by other articles:

				Y. Yokooji, H. Tomita, H. Atomi, and T. Imanaka Pantoate Kinase and Phosphopantothenate Synthetase, Two Novel Enzymes Necessary for CoA Biosynthesis in the Archaea J. Biol. Chem., October 9, 2009; 284(41): 28137 - 28145. [Abstract] [Full Text] [PDF]

				Z. Wu, C. Li, S. Lv, and B. Zhou Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model Hum. Mol. Genet., October 1, 2009; 18(19): 3659 - 3672. [Abstract] [Full Text] [PDF]

				F. Bosveld, A. Rana, P. E. van der Wouden, W. Lemstra, M. Ritsema, H. H. Kampinga, and O. C. M. Sibon De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system Hum. Mol. Genet., July 1, 2008; 17(13): 2058 - 2069. [Abstract] [Full Text] [PDF]

				K. Shinzawa, H. Sumi, M. Ikawa, Y. Matsuoka, M. Okabe, S. Sakoda, and Y. Tsujimoto Neuroaxonal Dystrophy Caused by Group VIA Phospholipase A2 Deficiency in Mice: A Model of Human Neurodegenerative Disease J. Neurosci., February 27, 2008; 28(9): 2212 - 2220. [Abstract] [Full Text] [PDF]

				I. Malik, J. Turk, D. J. Mancuso, L. Montier, M. Wohltmann, D. F. Wozniak, R. E. Schmidt, R. W. Gross, and P. T. Kotzbauer Disrupted Membrane Homeostasis and Accumulation of Ubiquitinated Proteins in a Mouse Model of Infantile Neuroaxonal Dystrophy Caused by PLA2G6 Mutations Am. J. Pathol., February 1, 2008; 172(2): 406 - 416. [Abstract] [Full Text] [PDF]

				B. Kazek, E. Jamroz, M. Gencik, A. Jezela Stanek, E. Marszal, and K. Wojaczynska-Stanek A Novel PANK2 Gene Mutation: Clinical and Molecular Characteristics of Patients Short Communication J Child Neurol, November 1, 2007; 22(11): 1256 - 1259. [Abstract] [PDF]

				B. S. Hong, G. Senisterra, W. M. Rabeh, M. Vedadi, R. Leonardi, Y.-M. Zhang, C. O. Rock, S. Jackowski, and H.-W. Park Crystal Structures of Human Pantothenate Kinases: INSIGHTS INTO ALLOSTERIC REGULATION AND MUTATIONS LINKED TO A NEURODEGENERATION DISORDER J. Biol. Chem., September 21, 2007; 282(38): 27984 - 27993. [Abstract] [Full Text] [PDF]

				R. Leonardi, C. O. Rock, S. Jackowski, and Y.-M. Zhang Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine PNAS, January 30, 2007; 104(5): 1494 - 1499. [Abstract] [Full Text] [PDF]

				Y.-M. Zhang, C. O. Rock, and S. Jackowski Biochemical Properties of Human Pantothenate Kinase 2 Isoforms and Mutations Linked to Pantothenate Kinase-associated Neurodegeneration J. Biol. Chem., January 6, 2006; 281(1): 107 - 114. [Abstract] [Full Text] [PDF]

				Y.-M. Zhang, C. O. Rock, and S. Jackowski Feedback Regulation of Murine Pantothenate Kinase 3 by Coenzyme A and Coenzyme A Thioesters J. Biol. Chem., September 23, 2005; 280(38): 32594 - 32601. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help