Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration
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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.
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Journal of Inherited Metabolic Disease
Volume 30, Issue 3 , pp 310-317
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- Springer Netherlands
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- 1. Departments of Medicine and Pediatrics, University of California, San Francisco, CA, USA
- 2. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
- 3. Institute for Human Genetics, UCSF, 513 Parnassus Avenue, HSE 901, San Francisco, CA, 94143-0794, USA