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Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Dec 19; Vol. 21 (24). Date of Electronic Publication: 2020 Dec 19. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Coenzyme A metabolism
Female
Hemochromatosis etiology
Homeostasis
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria genetics
Mitochondria metabolism
Mitochondria pathology
Mitochondrial Diseases etiology
Mitochondrial Diseases metabolism
Motor Disorders etiology
Motor Disorders metabolism
Coenzyme A Ligases physiology
Hemochromatosis pathology
Iron metabolism
Mitochondrial Diseases pathology
Motor Disorders pathology
Pantothenate Kinase-Associated Neurodegeneration complications
Synapsins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33352696
- Full Text :
- https://doi.org/10.3390/ijms21249707