Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation
Open accessAbstract
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.
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TfR trafficking is slightly altered in fibroblasts bearing NBIA-causing mutations.
“TfR trafficking is slightly altered in fibroblasts bearing NBIA-causing mutations (24).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [24]
The Results report significantly delayed transferrin recycling and impaired TfR1 trafficking in fibroblasts from NBIA subjects. They do not characterize the alteration as slight; the Discussion instead calls abnormal TfR1 recycling a common feature of NBIA. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPatients bearing compound heterozygous REPS1 point mutations show progressive cerebral and cerebellar atrophy.
“Patients bearing compound heterozygous REPS1 point mutations show progressive cerebral and cerebellar atrophy (24, 25).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [24]
The Results section reports two sisters with compound heterozygous REPS1 missense variants, supporting the mutation portion of the claim. The passages from our copy do not report progressive cerebral or cerebellar atrophy in those patients; searches for atrophy and MRI findings did not establish that portion. Page numbers were not available. (LLM, conf=0.85)
Experimental — accuracy not yet measuredREPS1 mutations cause neurodegenerative diseases.
“Because REPS1 mutations cause neurodegenerative diseases, next, we examined the functional role of the Reps1-Ralbp1-RalA module in neurons.”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [24]
REPS1 mutations in humans cause neurodegeneration with brain iron accumulation (NBIA).
“REPS1 mutations in humans cause neurodegeneration with brain iron accumulation (NBIA), a progressive neurodegenerative disease (24–26).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [24]
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Cites
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“either internalization of Tf receptor 1 (TfR1)-mediated endocytosis or non-Tf bound iron uptake (NTBI).(3,4) In living cells, newly imported iron is primarily used in the mitochondria and surpluses diverted to ferritin, a multimeric protein made up of two subunits, H-ferritin and L-ferritin.”
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Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module
Wang, S., Chen, X., Crisman, L., Dou, X., Winborn, C. S., Wan, C., Puscher, H., Yin, Q., Kennedy, M. J., & Shen, J. (2023) · Science Advances · doi:10.1126/sciadv.ade2540 · Cited by 14 · see citing works
- Authors
- Drecourt, A., Babdor, J., Dussiot, M., Petit, F., Goudin, N., Garfa-Traoré, M., Habarou, F., Bole-Feysot, C., Nitschké, P., Ottolenghi, C., Metodiev, M. D., Serre, V., Desguerre, I., Boddaert, N., Hermine, O., Munnich, A., & Rötig, A.
- Affiliations
- Sorbonne Paris Cité (FR)
- Centre National de la Recherche Scientifique (FR)
- Hôpital Necker-Enfants Malades (FR)
- Inserm (FR)
- Corresponding author
- Rötig, Agnès
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 102
- Issue
- 2
- Pages
- 266-277
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5985451
- OpenAlex
- W2785763347
- Cited by
- 100
- References
- 2
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 9 · 2023: 18 · 2022: 12 · 2021: 13 · 2020: 11 · 2019: 12 · 2018: 3
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the E-Rare project GENOMIT (01GM1207)
- Agence Nationale de la Recherche (ANR-10-IAHU-01)
- GIS-Institut des Maladies Rares
- Imagine Foundation
- ARC foundation
- GR-Ex LabEx
- ApoPharma
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- neurodegeneration with brain iron accumulation, transferrin receptor 1, palmitoylation, protein recycling, iron overload, CRAT, biallelic variants, artesunate, dystonia, basal ganglia, post-translational regulation
- MeSH terms
- Amino Acid Sequence, Brain, Calcium-Binding Proteins, Carrier Proteins, Endocytosis, Fibroblasts, HeLa Cells, Homeostasis, Humans, Iron, Mutation, Nerve Degeneration, Receptors, Transferrin, Transferrin, Lipoylation, HEK293 Cells
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