RESUMEN
Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.
Asunto(s)
Células Madre Pluripotentes Inducidas/citología , Enfermedades Mitocondriales/fisiopatología , Neurodegeneración Asociada a Pantotenato Quinasa/fisiopatología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Acetilcoenzima A/química , Adolescente , Biopsia , Encéfalo/metabolismo , Diferenciación Celular , Niño , Coenzima A/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Hierro/química , Cariotipificación , Peroxidación de Lípido , Masculino , Potencial de la Membrana Mitocondrial , Mitocondrias/patología , Mutación , NAD/química , Neuronas/metabolismo , Ácido Pantoténico/química , Fenotipo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Plásmidos/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Pantothenate kinase-associated neurodegeneration (PKAN) is an early onset and severely disabling neurodegenerative disease for which no therapy is available. PKAN is caused by mutations in PANK2, which encodes for the mitochondrial enzyme pantothenate kinase 2. Its function is to catalyze the first limiting step of Coenzyme A (CoA) biosynthesis. We generated induced pluripotent stem cells from PKAN patients and showed that their derived neurons exhibited premature death, increased ROS production, mitochondrial dysfunctions-including impairment of mitochondrial iron-dependent biosynthesis-and major membrane excitability defects. CoA supplementation prevented neuronal death and ROS formation by restoring mitochondrial and neuronal functionality. Our findings provide direct evidence that PANK2 malfunctioning is responsible for abnormal phenotypes in human neuronal cells and indicate CoA treatment as a possible therapeutic intervention.
Asunto(s)
Coenzima A/metabolismo , Neuronas/patología , Neurodegeneración Asociada a Pantotenato Quinasa/fisiopatología , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Muerte Celular , Células Cultivadas , Humanos , Mitocondrias/patología , Células Madre Pluripotentes/fisiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a rare heritable disease marked by dystonia and loss of movement control. In contrast to the well-known "Eye-of-the-Tiger" sign affecting the globus pallidus, little is known about other deviations of brain morphology, especially about grey matter changes. METHODS: We investigated 29 patients with PKAN and 29 age-matched healthy controls using Magnet Resonance Imaging and Voxel-Based Morphometry. RESULTS: As compared to controls, children with PKAN showed increased grey matter density in the putamen and nucleus caudatus and adults with PKAN showed increased grey matter density in the ventral part of the anterior cingulate cortex. A multiple regression analysis with dystonia score as predictor showed grey matter reduction in the cerebellum, posterior cingulate cortex, superior parietal lobule, pars triangularis and small frontal and temporal areas and an analysis with age as predictor showed grey matter decreases in the putamen, nucleus caudatus, supplementary motor area and anterior cingulate cortex. CONCLUSIONS: The grey matter increases may be regarded as a secondary phenomenon compensating the increased activity of the motor system due to a reduced inhibitory output of the globus pallidus. With increasing age, the grey matter reduction of cortical midline structures however might contribute to the progression of dystonic symptoms due to loss of this compensatory control.
Asunto(s)
Sustancia Gris/patología , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Agitación Psicomotora/patología , Adolescente , Adulto , Factores de Edad , Cerebelo/patología , Niño , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neurodegeneración Asociada a Pantotenato Quinasa/enzimología , Neurodegeneración Asociada a Pantotenato Quinasa/fisiopatología , Agitación Psicomotora/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: In a variety of dystonias, functional magnetic resonance imaging has shown deviations of cortical and basal ganglia activations within the motor network, which might cause the movement disturbances. Because these investigations have never been performed in secondary dystonia due to Pantothenate-Kinase Associated Neurodegeneration, we report our results in a small group of such patients from the Dominican Republic. METHODS: Functional magnetic resonance imaging was carried out in 7 patients with a genetically confirmed mutation of the PANK2 gene and a non-affected control group (matched pairs) using an event-related motor activation paradigm (hand movements). RESULTS: Compared to the control group (p ≤ 0.01), patients showed a larger amount of activated voxels starting in the contralateral cerebellum and contralateral premotor cortex 2 s before the actual hand movement. Whereas these "hyperactivations" gradually diminished over time, activations in the contralateral primary motor cortex and the supplementary motor area peaked during the next second and those of the contralateral putamen at the time of the actual hand movement. In a multiple regression analysis, all these areas correlated positively with the degree of dystonia of the contralateral arm as judged by the Burke-Fahn-Marsden-scale (p ≤ 0.001). CONCLUSION: As in other forms of dystonia, the increased activations of the motor system found in our patients could be related to the origin of the dystonic movements. Because in this condition the primary lesion affects the pallidum, a defect of the feed-back control mechanism between basal ganglia and cortex might be the responsible factor.
Asunto(s)
Cerebelo/irrigación sanguínea , Imagen por Resonancia Magnética , Corteza Motora/irrigación sanguínea , Movimiento/fisiología , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Neurodegeneración Asociada a Pantotenato Quinasa/fisiopatología , Adolescente , Mapeo Encefálico , Estudios de Casos y Controles , Cerebelo/fisiopatología , Femenino , Mano/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Corteza Motora/fisiopatología , Oxígeno/sangre , Adulto JovenRESUMEN
The EEG pattern of continuous, generalized, high-voltage fast rhythms without any reaction to eye-opening/closure, photic stimulation, or the sleep-awaking cycle was previously reported to be characteristic of infantile neuroaxonal dystrophy (INAD). However, we have observed such fast activity in one child with INAD and one with Menkes' kinky-hair syndrome. They both exhibited severe psychomotor disturbance, and their EEGs also included "frontal intermittent rhythmic delta activity (FIRDA)," a nonspecific EEG finding suggestive of organic encephalopathy. Since the continuous, generalized, high-voltage fast activity had features suggestive of spindles in both children, this EEG pattern is thought to actually represent "extreme spindles," and nonspecifically to indicate widespread organic brain damage.