Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model

Abstract

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.

Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic databases

“…This theory is strengthened by the fact that knockout of coasy is incompatible with life in mice. 26 In addition, a single report described four patients with biallelic LoF COASY variants affecting the C-terminus of the protein and prenatal onset of pontocerebellar hypoplasia, microcephaly and arthrogryposis. 27 In one case, where pregnancy was not early terminated, a boy was born, but died by the age of first month.…”

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

“…An example of a heterologous complementation approach refers to the GRACILE syndrome-related gene BCS1L, which encodes a mitochondrial chaperone required for the correct assembly of complex III being necessary for the incorporation of the Rieske FeS protein Rip1 [46][47][48]50,202]. Another example of validation where human cDNA was directly used is that of COASY [165,166], a gene encoding for the mitochondrial bifunctional enzyme, coenzyme A synthase [203], whose mutations are associated with the development of a form of neurodegeneration with brain iron accumulation (NBIA), namely Co-PAN (COASY protein-associated neurodegeneration) characterised by iron accumulation in the brain and the impairment of mitochondrial energy generation [165,204].…”

Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

“…Along this line of evidence, both deletion of the two enzymes (CAB4 and CAB5) exerting PPAT and DPCK activities in yeast [97] and effective downregulation of coasy expression in zebrafish embryos [98] were lethal, while expression of a mutant CAB5 or incomplete down-regulation led to milder phenotypes, with reduced CoA content. Di Meo et al have recently developed a mouse model with selective deletion of the Coasy gene in neurons [99]. These mice showed a severe phenotype with arrest of growth, sensorimotor defects, and dystonia-like movements, early death, even in the absence of neuronal loss.…”