title: 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.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.|Biotechnology Laboratory, Department of Diagnostics, Civic Hospital of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Biasiotto
authors.affiliation: Biotechnology Laboratory, Department of Diagnostics, Civic Hospital of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Di Lorenzo
authors.affiliation: Biotechnology Laboratory, Department of Diagnostics, Civic Hospital of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. isabella.zanella@unibs.it.|Biotechnology Laboratory, Department of Diagnostics, Civic Hospital of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy. isabella.zanella@unibs.it.
authors.forename: Isabella
authors.identifier: 0000-0003-3902-3376
authors.initials: I
authors.lastname: Zanella
mesh_terms: D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology
chemical_list: D005293:Ferritins; D007501:Iron
keywords: Autophagy; Ferritinophagy; Iron; Lysosome; NCOA4; Neurodegeneration; Nuclear receptor co-activator 4