Kurzawa-Akanbi, M;
Keogh, M;
Tsefou, E;
Ramsay, L;
Johnson, M;
Keers, S;
Ochieng, LWSA;
... Morris, CM; + view all
(2020)
Neuropathological and biochemical investigation of Hereditary Ferritinopathy cases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress.
Neuropathology and Applied Neurobiology
10.1111/nan.12634.
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Abstract
Aims Neuroferritinopathy (NF) or 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 intrinsic ability of FTL to self‐assemble. Ferritin aggregates were seen in neuronal and glial nuclei showing parallels with Huntington’s disease. There was neither 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 that these are not key mediators of neurodegeneration in HF, casting light on other neurodegenerative diseases characterized by iron deposition.
| Type: | Article |
|---|---|
| Title: | Neuropathological and biochemical investigation of Hereditary Ferritinopathy cases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/nan.12634 |
| Publisher version: | https://doi.org/10.1111/nan.12634 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Pathology, Neurosciences & Neurology, basal ganglia, ferritin, glia, iron, neurodegeneration, synuclein, tau, IRON HISTOCHEMISTRY, ALZHEIMERS-DISEASE, NUCLEAR FERRITIN, EPITHELIAL-CELLS, MUTANT FORM, NEUROFERRITINOPATHY, NEURODEGENERATION, POLYPEPTIDE, DEGRADATION, ACCUMULATION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > VP: Health UCL > Provost and Vice Provost Offices > VP: Health > Translational Research Office |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10105526 |
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