Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration
- 12 April 2007
- journal article
- research article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 30 (3), 310-317
- https://doi.org/10.1007/s10545-007-0560-8
Abstract
We asked whether a movement disorder could be elicited by deprivation of pantothenic acid (PA; vitamin B5), the substrate for the enzyme pantothenate kinase 2 (PANK2), which is deficient in the inherited neurological disorder PKAN (pantothenate kinase-associated neurodegeneration formerly called Hallervorden–Spatz syndrome). This study was undertaken because mice made null for Pank2 failed to show the neurological manifestations of the human disease. Wild-type and Pank2 mutant mice were fed pantothenic acid-deficient diets and were monitored for general health, fertility and movement compared with animals on control diets over time. Mice of both genotypes on PA-deficient diets exhibited poor grooming, greying of fur and decreased body weight. With PA deprivation, wild-type mice manifested azoospermia (a phenotype also seen in Pank2 mice) as well as a movement disorder with a low-lying pelvis and slow steps. Rear limbs appeared to drag and occasionally extended into unnatural postures for 16–17s duration, possibly indicative of dystonia. Movement disruption probably also occurs in PA-deprived Pank2 mutant mice, but they died precipitously before undergoing detailed analysis. Remarkably, restoration of dietary PA led to recovery of general health and grooming, weight gain, reversal of the movement disorder, and reappearance of mature sperm within 4 weeks. This study confirms the primacy of PA metabolism in the mechanism of disease in PKAN. PA deprivation provides a useful phenocopy for PKAN and allows us to test pharmacological and other interventional strategies in the treatment of this devastating disease.This publication has 20 references indexed in Scilit:
- Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitineProceedings of the National Academy of Sciences of the United States of America, 2007
- SCNM1, a Putative RNA Splicing Factor That Modifies Disease Severity in MiceScience, 2003
- An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondriaHuman Molecular Genetics, 2003
- Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosisProceedings of the National Academy of Sciences of the United States of America, 2001
- Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stressBiochemical Pharmacology, 1999
- Developmental expression of the mouse mottled and toxic milk genes suggests distinct functions for the Menkes and Wilson disease copper transportersHuman Molecular Genetics, 1997
- A Proposed Test Battery and Constellations of Specific Behavioral Paradigms to Investigate the Behavioral Phenotypes of Transgenic and Knockout MiceHormones and Behavior, 1997
- Impaired Cerebellar Synaptic Plasticity and Motor Performance in Mice Lacking the mGluR4 Subtype of Metabotropic Glutamate ReceptorJournal of Neuroscience, 1996
- Dietary Levels of Pantothenic Acid and Reproductive Performance of Female SwineJournal of Nutrition, 1955
- Pantothenic Acid Deficiency and Reproduction in the RatJournal of Nutrition, 1946