Iron and Neurodegeneration: Is Ferritinophagy the Link?

Abstract

Mounting evidence indicates that the lysosome-autophagy pathway plays a critical role in iron release from ferritin, the main iron storage cellular protein, hence in the distribution of iron to the cells. The recent identification of nuclear receptor co-activator 4 as the receptor for ferritin delivery to selective autophagy sheds further light on the understanding of the mechanisms underlying this pathway. The emerging view is that iron release from ferritin through the lysosomes is a general mechanism in normal and tumour cells of different tissue origins, but it has not yet been investigated in brain cells. Defects in the lysosome-autophagy pathway are often involved in the pathogenesis of neurodegenerative disorders, and brain iron homeostasis disruption is a hallmark of many of these diseases. However, in most cases, it has not been established whether iron dysregulation is directly involved in the pathogenesis of the diseases or if it is a secondary effect derived from other pathogenic mechanisms. The recent evidence of the crucial involvement of autophagy in cellular iron handling offers new perspectives about the role of iron in neurodegeneration, suggesting that autophagy dysregulation could cause iron dyshomeostasis. In this review, we recapitulate our current knowledge on the routes through which iron is released from ferritin, focusing on the most recent advances. We summarise the current evidence concerning lysosome-autophagy pathway dysfunctions and those of iron metabolism and discuss their potential interconnections in several neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases; amyotrophic lateral sclerosis; and frontotemporal lobar dementia.

Meta-analysis of brain iron levels of Parkinson’s disease patients determined by postmortem and MRI measurements

“…Iron dysregulation is frequently associated with neurodegenerative disorders, including Huntington disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration4041. Nonetheless, it remains unclear whether such defect is a cause or a consequence of neurodegeneration.…”

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

“…Growing evidence suggests that there is a direct correlation between sensitivity to iron and lysosomal dysfunction in various diseases such as Alzheimer disease. 57 Disruption of a lysosomal membrane protein leads to iron accumulation in Kupffer cells in the liver resulting in spontaneous liver fibrosis;…”

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

“…It is not surprising that CSF H-ferritin levels were also associated with more clinically significant comorbidity, as comorbidity has emerged as a powerful predictor of neurocognitive decline and is a common correlate of chronic inflammation in HIV+ persons [92]. Mechanisms other than inflammation may also explain increases in H-ferritin in CSF, including HIV-induced changes in autophagy or even ferritinophagy [93, 94]. Finally, associations with age, a strong risk factor for HAND, with both CSF transferrin and H-ferritin were pronounced before adjusting for Q Alb but lost significance after this adjustment; this begs the question whether the loss of iron regulation (or the loss of compartmentalization of iron) in the CSF due to age- or HIV-related damage to the blood–CSF barrier may in part mediate age-related neurocognitive decline.…”