Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration

Abstract

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.

Exploring Yeast as a Study Model of Pantothenate Kinase-Associated Neurodegeneration and for the Identification of Therapeutic Compounds

“…PKAN disorder is characterized by iron deposition in the brain although the relationship between CoA deficiency and iron accumulation remains unclear [ 22 ]. To investigate if PANK deficiency perturbs iron homeostasis in our model, the cellular response to iron was evaluated.…”

“…Currently for PKAN disease only symptomatic treatments are available [ 22 ]. Therapeutic approaches using panthethine [ 13 , 15 ], CoA [ 19 ], acetyl-4′-phosphopantetheine [ 23 ], fosmetpantotenate [ 24 ], pantothenate [ 21 ] and 4′-phosphopantetheine [ 12 ] have been proposed since a beneficial effect in different PKAN models has been reported.…”

Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model

“…Interestingly, iron accumulation precisely overlaps with augmented calcium and magnesium levels. Although our knowledge on the molecular mechanisms linking iron with calcium and magnesium accumulation in this disorder is limited, we have previously demonstrated a harmful iron–calcium connection in PKAN iPSCs-derived neurons, as well as brain calcification in both PKAN and CoPAN patients [ 3 , 29 ]. Associated to iron accumulation, here we found a profound and consistent alteration of iron homeostasis-regulating proteins, such as FtL, TfR1, and DMT1.…”

Complex dystonias: an update on diagnosis and care

“…Although causative genes are involved in different biochemical pathways, brain iron accumulation is a defining hallmark. Relevant pathophysiologic mechanisms include iron oxidation deficit, free, i.e., non-transferrin bound, toxic iron, oxidative stress, lysosomal or mitochondrial dysfunction, irregular calcium homeostasis, membrane remodeling, and autophagy (Levi et al 2019;Santambrogio et al 2015Santambrogio et al ,2020Brissot et al 2012;Maccarinelli et al 2015;Seibler et al 2018;Stelten et al 2019). Magnetic resonance imaging, particularly iron sensitive sequences, is very helpful, because most NBIAs have characteristic patterns of abnormalities (Lehericy et al 2020).…”

“…There is a pathognomonic "eye-of-the-tiger-sign" on T2-weighted images caused by focal iron accumulation in the globus pallidus, which occasionally disappears in the course of the disease (Baumeister et al 2005). The pathophysiology remains unclear, but mitochondrial dysfunction and impaired calcium homeostasis are discussed to play a pivotal role (Santambrogio et al 2015(Santambrogio et al , 2020. Treatment with deferiprone is still under investigation, but appears to slow disease progression with a good safety profile (Klopstock et al 2019;Rohani et al 2017;Zorzi et al 2011).…”