Inborn errors of CoA (coenzyme A) biosynthesis lead to neurodegenerative disorders in humans. PKAN (pantothenate kinase-associated neurodegeneration) manifests with damage to brain, retina and testis and is caused by mutations in PANK2, the gene encoding the mitochondrial form of pantothenate kinase, a key regulatory enzyme in CoA synthesis. Further attention has been focused on this pathway by the recent discovery that mutations in the gene encoding CoA synthase lead to a similar neurodegenerative disorder, raising the spectre of a common mechanism of pathogenesis. How do defects in CoA production result in neurodegeneration? Why are certain tissues and cell types selectively vulnerable? And what is the underlying neurodegenerative process? Answers to some of these questions have come from animal models of disease, including flies and mice, as well as directly from humans. The damaged tissue types share key features that are likely to contribute to their selective vulnerability. These include the presence of a blood–tissue barrier, the milieu with respect to oxidative stress, tissue metabolic demand, relative expression of genes encoding similar proteins in these tissues and cell membrane composition. Substantial progress in understanding these important neurometabolic disorders has been made since the first gene discovery more than a decade ago. With rational therapeutics now in development for PKAN, we foresee prevention of neurodegeneration and hope for neuroregeneration or neuro-rescue.
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Conference Article|
August 11 2014
Defective pantothenate metabolism and neurodegeneration
Susan J. Hayflick
Susan J. Hayflick
1
*Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, U.S.A.
†Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, U.S.A.
‡Department of Neurology, Oregon Health & Science University, Portland, OR 97239, U.S.A.
1emailhayflick@ohsu.edu
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Publisher: Portland Press Ltd
Received:
April 14 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (4): 1063–1068.
Article history
Received:
April 14 2014
Citation
Susan J. Hayflick; Defective pantothenate metabolism and neurodegeneration. Biochem Soc Trans 1 August 2014; 42 (4): 1063–1068. doi: https://doi.org/10.1042/BST20140098
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