Cargando…
Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease
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-synu...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8878351/ https://www.ncbi.nlm.nih.gov/pubmed/35216492 http://dx.doi.org/10.3390/ijms23042378 |
_version_ | 1784658640282583040 |
---|---|
author | Boag, Matthew K. Roberts, Angus Uversky, Vladimir N. Ma, Linlin Richardson, Des R. Pountney, Dean L. |
author_facet | Boag, Matthew K. Roberts, Angus Uversky, Vladimir N. Ma, Linlin Richardson, Des R. Pountney, Dean L. |
author_sort | Boag, Matthew K. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8878351 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88783512022-02-26 Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease Boag, Matthew K. Roberts, Angus Uversky, Vladimir N. Ma, Linlin Richardson, Des R. Pountney, Dean L. Int J Mol Sci Review 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. MDPI 2022-02-21 /pmc/articles/PMC8878351/ /pubmed/35216492 http://dx.doi.org/10.3390/ijms23042378 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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/). |
spellingShingle | Review Boag, Matthew K. Roberts, Angus Uversky, Vladimir N. Ma, Linlin Richardson, Des R. Pountney, Dean L. Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease |
title | Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease |
title_full | Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease |
title_fullStr | Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease |
title_full_unstemmed | Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease |
title_short | Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease |
title_sort | ferritinophagy and α-synuclein: pharmacological targeting of autophagy to restore iron regulation in parkinson’s disease |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8878351/ https://www.ncbi.nlm.nih.gov/pubmed/35216492 http://dx.doi.org/10.3390/ijms23042378 |
work_keys_str_mv | AT boagmatthewk ferritinophagyandasynucleinpharmacologicaltargetingofautophagytorestoreironregulationinparkinsonsdisease AT robertsangus ferritinophagyandasynucleinpharmacologicaltargetingofautophagytorestoreironregulationinparkinsonsdisease AT uverskyvladimirn ferritinophagyandasynucleinpharmacologicaltargetingofautophagytorestoreironregulationinparkinsonsdisease AT malinlin ferritinophagyandasynucleinpharmacologicaltargetingofautophagytorestoreironregulationinparkinsonsdisease AT richardsondesr ferritinophagyandasynucleinpharmacologicaltargetingofautophagytorestoreironregulationinparkinsonsdisease AT pountneydeanl ferritinophagyandasynucleinpharmacologicaltargetingofautophagytorestoreironregulationinparkinsonsdisease |