Cargando…
The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease
Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α‐synuclein accumulation has long been established to play a causal role in the disease, it al...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496448/ https://www.ncbi.nlm.nih.gov/pubmed/31991026 http://dx.doi.org/10.1111/ejn.14689 |
_version_ | 1783583099070709760 |
---|---|
author | van der Vlag, Marc Havekes, Robbert Heckman, Pim R. A. |
author_facet | van der Vlag, Marc Havekes, Robbert Heckman, Pim R. A. |
author_sort | van der Vlag, Marc |
collection | PubMed |
description | Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α‐synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca(2+) ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α‐synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD‐related genes Parkin, PINK1 and DJ‐1. We establish that these mutant varieties can set in motion the same degenerative process involving α‐synuclein, cytosolic catecholamines and Ca(2+). Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ‐1 model organisms often lack a convincing PD‐like phenotype. |
format | Online Article Text |
id | pubmed-7496448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74964482020-09-25 The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease van der Vlag, Marc Havekes, Robbert Heckman, Pim R. A. Eur J Neurosci Clinical and Translational Neuroscience Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α‐synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca(2+) ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α‐synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD‐related genes Parkin, PINK1 and DJ‐1. We establish that these mutant varieties can set in motion the same degenerative process involving α‐synuclein, cytosolic catecholamines and Ca(2+). Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ‐1 model organisms often lack a convincing PD‐like phenotype. John Wiley and Sons Inc. 2020-02-06 2020-08 /pmc/articles/PMC7496448/ /pubmed/31991026 http://dx.doi.org/10.1111/ejn.14689 Text en © 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Clinical and Translational Neuroscience van der Vlag, Marc Havekes, Robbert Heckman, Pim R. A. The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease |
title | The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease |
title_full | The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease |
title_fullStr | The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease |
title_full_unstemmed | The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease |
title_short | The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease |
title_sort | contribution of parkin, pink1 and dj‐1 genes to selective neuronal degeneration in parkinson's disease |
topic | Clinical and Translational Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496448/ https://www.ncbi.nlm.nih.gov/pubmed/31991026 http://dx.doi.org/10.1111/ejn.14689 |
work_keys_str_mv | AT vandervlagmarc thecontributionofparkinpink1anddj1genestoselectiveneuronaldegenerationinparkinsonsdisease AT havekesrobbert thecontributionofparkinpink1anddj1genestoselectiveneuronaldegenerationinparkinsonsdisease AT heckmanpimra thecontributionofparkinpink1anddj1genestoselectiveneuronaldegenerationinparkinsonsdisease AT vandervlagmarc contributionofparkinpink1anddj1genestoselectiveneuronaldegenerationinparkinsonsdisease AT havekesrobbert contributionofparkinpink1anddj1genestoselectiveneuronaldegenerationinparkinsonsdisease AT heckmanpimra contributionofparkinpink1anddj1genestoselectiveneuronaldegenerationinparkinsonsdisease |