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

Abstract

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 andstudy 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 suggestingoligodendrocytes, withaccompanying neuronal pathology and neuronal loss. Neuronsstill 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 FTLcan aggregate, reflecting theintrinsicability of FTL to self‐assemble.Ferritin aggregates were seenin neuronal and glial nuclei showing parallels with Huntington's disease. There was no evidence of oxidative stress activation nor any significant mitochondrial pathologyin 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.