Abstract
BackgroundPantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed.MethodsWe applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671.Results1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre+Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre+Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment.ConclusionsBBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.
Highlights
Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis
We used proton magnetic resonance spectroscopy (1H MRS) to evaluate the brain metabolic derangements that are associated with neuronal CoA deficiency in this mouse model, with and without treatment with a newly developed Pantazine, BBP-671. 1H MRS is advantageous for this study because it permits the noninvasive examination of the most abundant cerebral metabolites in vivo [11]
There is a clear reduction in the Glx/total creatine (tCr), N-acetyl aspartate (NAA)/tCr and lactate/tCr ratios in the midbrains of the SynCre+Pank1,2 neuronal dKO mice compared to WT (Wildtype)
Summary
Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. We used proton magnetic resonance spectroscopy (1H MRS) to evaluate the brain metabolic derangements that are associated with neuronal CoA deficiency in this mouse model, with and without treatment with a newly developed Pantazine, BBP-671. 1H MRS is advantageous for this study because it permits the noninvasive examination of the most abundant cerebral metabolites in vivo [11]
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