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Neuropathological and Biochemical Investigation of Hereditary Ferritinopathycases with Ferritin Light Chain Mutation: Prominent Protein Aggregation in the Absence of Major Mitochondrial or Oxidative Stress

Lookup NU author(s): Dr Marzena Kurzawa-Akanbi, Dr Michael Keogh, Eliona Tsefou, Lynne Ramsay, Mary Johnson, Dr Preeti Singh, Dr Angela Pyle, Professor Gavin Hudson, Professor Johannes Attems, Professor Sir John BurnORCiD, Professor Patrick Chinnery, Dr Christopher Morris



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Aims: Neuroferritinopathyor Hereditary Ferritinopathy (HF)is an autosomal dominant movement disorder due to mutation in the light chain of the iron storage protein ferritin (FTL).HF is the only late‐onset neurodegeneration with brain iron accumulation disorder and study of HF offers a unique opportunity to understand the role of iron in more common neurodegenerative syndromes. Methods: We carried out pathological and biochemical studies of six individuals with the same pathogenic FTL mutation. Results: CNS pathological changes were most prominent in the basal ganglia and cerebellar dentate, echoing the normal pattern of brain iron accumulation. Accumulation of ferritin and iron was conspicuous in cells with a phenotype suggesting oligodendrocytes, with accompanying neuronal pathology and neuronal loss. Neurons still survived however, despite extensive adjacent glial iron deposition, suggesting neuronal loss is a downstream event. Typical age‐related neurodegenerative pathology was not normally present. Uniquely, the extensive aggregates of ubiquitinated ferritin identified indicate that abnormal FTL can aggregate, reflecting the intrinsicability of FTL to self‐assemble. Ferritin aggregates were seen in neuronal and glial nuclei showing parallels with Huntington's disease. There was no evidence of oxidative stress activation nor any significant mitochondrial pathology in the affected basal ganglia. Conclusions: HF shows hallmarks of a protein aggregation disorder, in addition to iron accumulation. Degeneration in HF is not accompanied by age‐related neurodegenerative pathology and the lack of evidence of oxidative stress and mitochondrial damage suggests these are not key mediators of neurodegeneration in HF, casting light on other neurodegenerative diseases characterised by iron deposition.

Publication metadata

Author(s): Kurzawa-Akanbi M, Keogh M, Tsefou E, Ramsay L, Johnson M, Keers S, Ochieng LW, McNair A, Singh P, Khan A, Pyle A, Hudson G, Ince PG, Attems J, Burn J, Chinnery PF, Morris CM

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2021

Volume: 47

Issue: 1

Pages: 26-42

Print publication date: 01/02/2021

Online publication date: 28/05/2020

Acceptance date: 28/05/2020

Date deposited: 16/06/2020

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley-Blackwell Publishing, Inc.


DOI: 10.1111/nan.12634

PubMed id: 32464705


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