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Open AccessArticle

Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration

1
IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
2
Division of Neuroscience, Vita-Salute San Raffaele University, 20132 Milan, Italy
3
Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy
4
Department of Neuroscience, University of Padua, 35122 Padua, Italy
5
Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy
6
Institute of Neuroscience, National Research Council, 20132 Milan, Italy
7
Department of Medical and Surgical Specialities, University of Brescia, 25123 Brescia, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3664; https://doi.org/10.3390/ijms21103664
Received: 28 April 2020 / Revised: 15 May 2020 / Accepted: 19 May 2020 / Published: 22 May 2020
Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease. View Full-Text
Keywords: neurodegeneration; PKAN (pantothenate kinase-associated neurodegeneration); NBIA (neurodegeneration with brain iron accumulation); iron; calcium; iPSC (induced pluripotent stem cells) neurodegeneration; PKAN (pantothenate kinase-associated neurodegeneration); NBIA (neurodegeneration with brain iron accumulation); iron; calcium; iPSC (induced pluripotent stem cells)
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Santambrogio, P.; Ripamonti, M.; Paolizzi, C.; Panteghini, C.; Carecchio, M.; Chiapparini, L.; Raimondi, M.; Rubio, A.; Di Meo, I.; Cozzi, A.; Taverna, S.; De Palma, G.; Tiranti, V.; Levi, S. Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration. Int. J. Mol. Sci. 2020, 21, 3664.

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