Neuronal ablation of coa synthase causes motor deficits, iron dyshomeostasis, and mitochondrial dysfunctions in a copan mouse model: International Journal of Molecular Sciences

I. Di Meo, C. Cavestro, S. Pedretti, T. Fu, S. Ligorio, A. Manocchio, L. Lavermicocca, P. Santambrogio, M. Ripamonti, S. Levi, S. Ayciriex, N. Mitro, V. Tiranti

Research output: Contribution to journalArticlepeer-review


COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Original languageEnglish
Article number9707
Number of pages20
JournalInt. J. Mol. Sci.
Issue number24
Publication statusPublished - 2020


  • Coenzyme A
  • CoPAN (COASY protein-associated neurodegeneration)
  • Iron
  • Mitochondria
  • Mouse model
  • NBIA (neurodegeneration with brain iron accumulation)
  • Neurodegeneration
  • 4 hydroxynonenal
  • calcium
  • carbonyl derivative
  • CD71 antigen
  • coenzyme A
  • coenzyme A synthase
  • copper zinc superoxide dismutase
  • ferritin
  • ferritin heavy chain
  • ferritin light chain
  • ferroportin
  • iron
  • iron regulatory protein 1
  • iron regulatory protein 2
  • magnesium
  • messenger RNA
  • natural resistance associated macrophage protein 2
  • synthetase
  • unclassified drug
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • autosomal recessive disorder
  • biosynthesis
  • brain level
  • cell structure
  • coasy protein associated neurodegeneration
  • controlled study
  • degenerative disease
  • disorders of mitochondrial functions
  • enzyme deficiency
  • extrapyramidal symptom
  • female
  • ferroptosis
  • inborn error of metabolism
  • iron homeostasis
  • iron metabolism disorder
  • iron overload
  • lipid peroxidation
  • male
  • mitochondrial respiration
  • mitochondrion
  • motor dysfunction
  • mouse
  • neuropathology
  • nonhuman
  • oxidative stress
  • protein acetylation
  • protein carbonylation


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