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1.
Mamm Genome ; 32(5): 332-349, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043061

RESUMO

Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.


Assuntos
Proteínas de Transporte/genética , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Fenótipo
2.
Biochim Biophys Acta Mol Basis Dis ; 1863(9): 2220-2228, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28545977

RESUMO

Glutaric aciduria type I (GA-I) is a rare organic aciduria caused by the autosomal recessive inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). GCDH deficiency leads to disruption of l-lysine degradation with characteristic accumulation of glutarylcarnitine and neurotoxic glutaric acid (GA), glutaryl-CoA, 3-hydroxyglutaric acid (3-OHGA). DHTKD1 acts upstream of GCDH, and its deficiency leads to none or often mild clinical phenotype in humans, 2-aminoadipic 2-oxoadipic aciduria. We hypothesized that inhibition of DHTKD1 may prevent the accumulation of neurotoxic dicarboxylic metabolites suggesting DHTKD1 inhibition as a possible treatment strategy for GA-I. In order to validate this hypothesis we took advantage of an existing GA-I (Gcdh-/-) mouse model and established a Dhtkd1 deficient mouse model. Both models reproduced the biochemical and clinical phenotype observed in patients. Under challenging conditions of a high lysine diet, only Gcdh-/- mice but not Dhtkd1-/- mice developed clinical symptoms such as lethargic behaviour and weight loss. However, the genetic Dhtkd1 inhibition in Dhtkd1-/-/Gcdh-/- mice could not rescue the GA-I phenotype. Biochemical results confirm this finding with double knockout mice showing similar metabolite accumulations as Gcdh-/- mice with high GA in brain and liver. This suggests that DHTKD1 inhibition alone is not sufficient to treat GA-I, but instead a more complex strategy is needed. Our data highlights the many unresolved questions within the l-lysine degradation pathway and provides evidence for a so far unknown mechanism leading to glutaryl-CoA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Cetona Oxirredutases/deficiência , Fígado/metabolismo , Lisina/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Animais , Encéfalo/patologia , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/terapia , Modelos Animais de Doenças , Glutaril-CoA Desidrogenase/genética , Glutaril-CoA Desidrogenase/metabolismo , Cetona Oxirredutases/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout
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