Abstract
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.
Highlights
Pantothenate kinase-associated neurodegeneration (PKAN; OMIM *606157) is an autosomal recessive movement disorder caused by mutations in PANK2 (Zhou et al, 2001)
To verify whether PANK2 deficiency leads to impairment of these mitochondrial pathways, we investigated the activity of two ISCcontaining enzymes and the heme content in human induced pluripotent stem cell (hiPSC)-derived neurons
One prevailing hypothesis proposes that the imbalance of Coenzyme A (CoA) pool could impair lipid homeostasis, resulting in membrane dysfunction and mitochondrial alteration including energy deficiency and impairment of oxidative status and iron metabolism
Summary
Pantothenate kinase-associated neurodegeneration (PKAN; OMIM *606157) is an autosomal recessive movement disorder caused by mutations in PANK2 (Zhou et al, 2001) It belongs to a heterogeneous group of neurodegenerative diseases, collectively known as neurodegeneration with brain iron accumulation (NBIA), which are characterized by severe iron overload in specific brain regions, neurodegeneration and extrapyramidal dysfunction (Hayflick et al, 2006; Levi & Finazzi, 2014). CoA is a key molecule involved in more than 100 metabolic processes, among which CoA derivatives are crucial substrates for ATP generation via the tricarboxylic acid cycle, fatty acid metabolism, cholesterol and ketone body biosynthesis, and histone and non-histone protein acetylation (Siudeja et al, 2011; Akram, 2014) These processes are vital for any cell type, it remains unexplained why the disease affects primarily the central nervous system
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