Deletion of Pantothenate Kinase 1 and 2 in Mice Results in a Neurodegenerative Phenotype and Death during Postnatal Development

Pantothenate kinase (PanK) catalyzes the first step in coenzyme A (CoA) biosynthesis. CoA is an important cofactor involved in a number of metabolic pathways. Three genes express the four catalytically active isoforms of mammalian PanK: PanK1α, 1β, 2 and 3. Mutations in the human PANK2 gene results in a neurodegenerative disease called PKAN (Pantothenate Kinase Associated Neurodegeneration). PKAN shares a number of features with Parkinson's disease, including dystonia, dementia, brain iron accumulation and the degeneration of dopaminergic neurons. Deletion of the mouse Pank2 gene did not result in a PKAN‐like phenotype. We generated a Pank1/Pank2 double knockout (dKO) mouse in an effort to generate an animal model for PKAN and to investigate the effect of reduced cellular CoA levels. The dKO mice had reduced liver CoA levels and accumulated triglycerides, corresponding to a defect in fatty acid oxidation. They were severely affected in their postnatal development and survival becoming severely hypoglycemic prior to death within 17 days. Brain CoA levels were significantly decreased and the dKO mice exhibited hind‐limb dragging prior to death, a symptom of neuromuscular dysfunction reminiscent of PKAN disease. The results indicate that reduction of CoA levels and a decrease in brain and liver CoA‐dependant metabolism may be involved in the progression of PKAN disease. (Supported by NIH GM062896 and ALSAC)