Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency

Yanan Li, Jeffrey Steinberg, Zane Coleman, Shubo Wang, Chitra Subramanian, Yimei Li, Zoltan Patay, Walter Akers, Charles O. Rock, Suzanne Jackowski, Puneet Bagga

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Pantothenate 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. Methods: We applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671. Results: 1H 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. Conclusions: BBP-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.

Original languageEnglish (US)
Article number103
JournalJournal of Translational Medicine
Volume20
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Keywords

  • H magnetic resonance spectroscopy
  • Coenzyme A
  • Metabolites
  • Neurodegeneration
  • Pantothenate kinase
  • Pantothenate kinase-associated neurodegeneration
  • Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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