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PKAN disease is caused by mutations in the PANK2 gene, encoding the mitochondrial enzyme pantothenate kinase 2, catalyzing the first and key reaction in Coenzyme A (CoA) biosynthetic process. This disorder is characterized by progressive neurodegeneration and excessive iron deposition in the brain. The pathogenic mechanisms of PKAN are still unclear, and the available therapies are only symptomatic. Although iron accumulation is a hallmark of PKAN, its relationship with CoA dysfunction is not clear. We have previously developed hiPS-derived astrocytes from PKAN patients showing iron overload, thus recapitulating the human phenotype. In this work, we demonstrated that PKAN astrocytes presented an increase in transferrin uptake, a key route for cellular iron intake via transferrin receptor-mediated endocytosis of transferrin-bound iron. Investigation of constitutive exo-endocytosis and vesicular dynamics, exploiting the activity-enriching biosensor SynaptoZip, led to the finding of a general impairment in the constitutive endosomal trafficking in PKAN astrocytes. CoA and 4-phenylbutyric acid treatments were found to be effective in partially rescuing the aberrant vesicular behavior and iron intake. Our results demonstrate that the impairment of CoA biosynthesis could interfere with pivotal intracellular mechanisms involved in membrane fusions and vesicular trafficking, leading to an aberrant transferrin receptor-mediated iron uptake. [ABSTRACT FROM AUTHOR]

PKAN disease is caused by mutations in the PANK2 gene, encoding the mitochondrial enzyme pantothenate kinase 2, catalyzing the first and key reaction in Coenzyme A (CoA) biosynthetic process. This disorder is characterized by progressive neurodegeneration and excessive iron deposition in the brain. The pathogenic mechanisms of PKAN are still unclear, and the available therapies are only symptomatic. Although iron accumulation is a hallmark of PKAN, its relationship with CoA dysfunction is not clear. We have previously developed hiPS-derived astrocytes from PKAN patients showing iron overload, thus recapitulating the human phenotype. In this work, we demonstrated that PKAN astrocytes presented an increase in transferrin uptake, a key route for cellular iron intake via transferrin receptor-mediated endocytosis of transferrin-bound iron. Investigation of constitutive exo-endocytosis and vesicular dynamics, exploiting the activity-enriching biosensor SynaptoZip, led to the finding of a general impairment in the constitutive endosomal trafficking in PKAN astrocytes. CoA and 4-phenylbutyric acid treatments were found to be effective in partially rescuing the aberrant vesicular behavior and iron intake. Our results demonstrate that the impairment of CoA biosynthesis could interfere with pivotal intracellular mechanisms involved in membrane fusions and vesicular trafficking, leading to an aberrant transferrin receptor-mediated iron uptake.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive disease characterized by iron accumulation in the brain due to PANK2 gene mutation. The typical "eye-of-the-tiger" sign is the characteristic manifestation of brain magnetic resonance imaging (MRI). We report a Chinese patient with atypical PKAN whose brain MRI scans displayed the typical "eye-of-the-tiger" sign in bilateral pallidum. Genetic analysis identified a compound heterozygous mutation (c. 629-2A > T, c. 1130T > C) for the PANK2 gene. These two mutations were further demonstrated in his parents and other relatives. [ABSTRACT FROM AUTHOR]

Pantothenate kinase-associated neurodegeneration ( PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, because of mutations in the PANK2 gene. Phenotypic and genotypic characteristics of 11 patients from five Mexican families with PKAN disease are reported. Sequencing of PANK2 confirmed the diagnosis. The 11 patients had dysarthria associated with dystonia and Parkinsonism in six. Brain magnetic resonance imaging ( MRI) showed the 'eye-of-the-tiger' sign in all patients. Three different mutations were identified, a novel one (p. A469P) and two (p. G219V and p. N404I) very rare. Homozygous sibs for the p. G219V mutation had a severe disease progression with early death. Dystonia predominated in the p. A469P/p. N404I compound heterozygous patients. Homozygous for p. N404I showed Parkinsonism, tics and personality and speech disorders. Early and late disease onset and variable expression was present in carriers of the different identified mutations. The 'eye-of-the-tiger' is an excellent neuroimaging hallmark to predict PANK2 mutations. We detected a 'cluster' of patients harboring the p. N404I mutation, strongly suggesting a founder effect for this mutation. This is the first familial clinical-genetic PKAN disease study accomplished in Mexico. [ABSTRACT FROM AUTHOR]