Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration

• DOI: 10.3390/ijms21103664
• Publication Date: 2020-05-25T10:43:40Z
• Authors: Paolo Santambrogio; Maddalena Ripamonti; Chiara Paolizzi; Celeste Panteghini; Miryam Carecchio; Luisa Chiapparini; Marzia Raimondi; Alicia Rubio; Ivano Di Meo; Anna Cozzi; Stefano Taverna; Giuseppe De Palma; Valeria Tiranti; Sonia Levi
• Keywords: IPSC (induced pluripotent stem cells); Male; 0301 basic medicine; Cytoplasm; Adolescent; Calcium; IPSC (induced pluripotent stem cells); Iron; NBIA (neurodegeneration with brain iron accumulation); Neurodegeneration; PKAN (pantothenate kinase-associated neurodegeneration); Adolescent; Brain; Calcium; Calpain; Child; Child, Preschool; Cohort Studies; Cytoplasm; Female; Homeostasis; Humans; Induced Pluripotent Stem Cells; Infant; Iron; Magnetic Resonance Imaging; Male; Mass Spectrometry; Microscopy, Electron; Mitochondria; Neurons; Pantothenate Kinase-Associated Neurodegeneration; Phosphotransferases (Alcohol Group Acceptor); Tomography, X-Ray Computed; Young Adult; Iron; Induced Pluripotent Stem Cells; Calcium; IPSC (induced pluripotent stem cells); Iron; NBIA (neurodegeneration with brain iron accumulation); Neurodegeneration; PKAN (pantothenate kinase-associated neurodegeneration);; NBIA (neurodegeneration with brain iron accumulation); Article; Mass Spectrometry; Cohort Studies; 03 medical and health sciences; iron; Homeostasis; Humans; Neurodegeneration; PKAN (pantothenate kinase-associated neurodegeneration); Child; Neurons; calcium; Calpain; neurodegeneration; Brain; Infant; iPSC (induced pluripotent stem cells); Magnetic Resonance Imaging; Calcium; IPSC (induced pluripotent stem cells); Iron; NBIA (neurodegeneration with brain iron accumulation); Neurodegeneration; PKAN (pantothenate kinase-associated neurodegeneration); Mitochondria; 3. Good health; Microscopy, Electron; Child, Preschool; Calcium; Female

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.