Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2 (PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there a standard course of treatment. In the current work, we describe that fibroblasts derived from patients harbouring PANK2 mutations can reproduce many of the cellular pathological alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme substrate, was able to correct all pathological alterations in responder mutant fibroblasts with residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of pantothenate in particular mutations was also confirmed in induced neurons obtained by direct reprograming of mutant fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels of PANK2 in selected mutations. These results encourage us to propose our screening model as a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of pantothenate.

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Acknowledgements

We thank María Pilar Burgos Domenech from IRNAS (Instituto de Recursos Naturales y Agrobiología de Sevilla) for her help with the ICP-MS assays and Carmen Jiménez de Haro from Instituto de Ciencia de Materiales de Sevilla (ICMS-US-CSIC) for her help with the SEM/EDX assays. We also thank Drs. Javier Abril Jaramillo, Anabel Vintimilla, Luis González Gutiérrez Solana, Pablo Mir, Marcos Madruga, Silvia Jesús, and Isidoro Caraballo for their support to the project.

Funding

This work was supported by FIS PI16/00786 grant, Instituto de Salud Carlos III, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyectos de Investigación de Excelencia de la Junta de Andalucía CTS-5725 and BIO-122, DGICYT BFU2015-64536-R, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro).

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Correspondence to José A. Sánchez-Alcázar.

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Álvarez-Córdoba, M., Fernández Khoury, A., Villanueva-Paz, M. et al. Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation. Mol Neurobiol 56, 3638–3656 (2019). https://doi.org/10.1007/s12035-018-1333-0

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Keywords

  • Pantothenate kinase
  • Coenzyme A
  • Mitochondria
  • Pantothenate
  • Induced neurons