Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation

• Published in: American journal of human genetics Vol. 102; no. 2; pp. 266 - 277
• Main Authors: Drecourt, Anthony, Babdor, Joël, Dussiot, Michael, Petit, Floriane, Goudin, Nicolas, Garfa-Traoré, Meriem, Habarou, Florence, Bole-Feysot, Christine, Nitschké, Patrick, Ottolenghi, Chris, Metodiev, Metodi D., Serre, Valérie, Desguerre, Isabelle, Boddaert, Nathalie, Hermine, Olivier, Munnich, Arnold, Rötig, Agnès
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018; Elsevier
• Subjects: Amino Acid Sequence; artesunate; Brain - pathology; Carrier Proteins - genetics; Endocytosis; Fibroblasts - metabolism; HEK293 Cells; HeLa Cells; Homeostasis; Humans; Iron - metabolism; iron overload; Lipoylation; mitochondria; Mutation - genetics; NBIA; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; neurodegeneration with brain iron accumulation; palmitoylation; Receptors, Transferrin - chemistry; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Transferrin - metabolism; transferrin receptor; iron overload; neurodegeneration with brain iron accumulation; artesunate; mitochondria; NBIA; transferrin receptor; palmitoylation
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2018.01.003

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.