Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease

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Boag, Matthew K
Roberts, Angus
Uversky, Vladimir N
Ma, Linlin
Richardson, Des R
Pountney, Dean L
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2022
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Abstract

A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated α-synuclein inhibits SNARE protein complexes and destabilizes microtubules to halt vesicular trafficking systems, including that of autophagy effectively. The scope of this review is to describe the physiological and pathological relationship between iron regulation and α-synuclein, providing a detailed understanding of iron metabolism within nigral neurons. The underlying mechanisms of autophagy and ferritinophagy are explored in the context of PD, identifying potential therapeutic targets for future investigation.

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International Journal of Molecular Sciences

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23

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4

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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Genetics

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Biochemistry and cell biology

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Medicinal and biomolecular chemistry

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Life Sciences & Biomedicine

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Biochemistry & Molecular Biology

Chemistry, Multidisciplinary

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Boag, MK; Roberts, A; Uversky, VN; Ma, L; Richardson, DR; Pountney, DL, Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease, International Journal of Molecular Sciences, 2022, 23 (4), pp. 2378

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