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Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
Parkinson’s disease (PD) is characterized by massive degeneration of dopaminergic neurons in the substantia nigra. Whereas the majority of PD cases are sporadic, about 5–10% of cases are familial and associated with genetic factors. The loss of parkin or PINK1, two such factors, leads to an early on...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715719/ https://www.ncbi.nlm.nih.gov/pubmed/23882257 http://dx.doi.org/10.3389/fneur.2013.00100 |
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author | Grenier, Karl McLelland, Gian-Luca Fon, Edward A. |
author_facet | Grenier, Karl McLelland, Gian-Luca Fon, Edward A. |
author_sort | Grenier, Karl |
collection | PubMed |
description | Parkinson’s disease (PD) is characterized by massive degeneration of dopaminergic neurons in the substantia nigra. Whereas the majority of PD cases are sporadic, about 5–10% of cases are familial and associated with genetic factors. The loss of parkin or PINK1, two such factors, leads to an early onset form of PD. Importantly, recent studies have shown that parkin functions downstream of PINK1 in a common genetic pathway affecting mitochondrial homeostasis. More precisely, parkin has been shown to mediate the autophagy of damaged mitochondria (mitophagy) in a PINK1-dependent manner. However, much of the work characterizing this pathway has been carried out in immortalized cell lines overexpressing high levels of parkin. In contrast, whether or how endogenous parkin and PINK1 contribute to mitophagy in neurons is much less clear. Here we review recent work addressing the role of parkin/PINK1-dependent mitophagy in neurons. Clearly, it appears that mitophagy pathways differ spatially and kinetically in neurons and immortalized cells, and therefore might diverge in their ultimate outcome and function. While evidence suggests that parkin can translocate to mitochondria in neurons, the function and mechanism of mitophagy downstream of parkin recruitment in neurons remains to be clarified. Moreover, it is noteworthy that most work has focused on the downstream signaling events in parkin/PINK1 mitophagy, whereas the upstream signaling pathways remain comparatively poorly characterized. Identifying the upstream signaling mechanisms that trigger parkin/PINK1 mitophagy will help to explain the nature of the insults affecting mitochondrial function in PD, and a better understanding of these pathways in neurons will be the key in identifying new therapeutic targets in PD. |
format | Online Article Text |
id | pubmed-3715719 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-37157192013-07-23 Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? Grenier, Karl McLelland, Gian-Luca Fon, Edward A. Front Neurol Neuroscience Parkinson’s disease (PD) is characterized by massive degeneration of dopaminergic neurons in the substantia nigra. Whereas the majority of PD cases are sporadic, about 5–10% of cases are familial and associated with genetic factors. The loss of parkin or PINK1, two such factors, leads to an early onset form of PD. Importantly, recent studies have shown that parkin functions downstream of PINK1 in a common genetic pathway affecting mitochondrial homeostasis. More precisely, parkin has been shown to mediate the autophagy of damaged mitochondria (mitophagy) in a PINK1-dependent manner. However, much of the work characterizing this pathway has been carried out in immortalized cell lines overexpressing high levels of parkin. In contrast, whether or how endogenous parkin and PINK1 contribute to mitophagy in neurons is much less clear. Here we review recent work addressing the role of parkin/PINK1-dependent mitophagy in neurons. Clearly, it appears that mitophagy pathways differ spatially and kinetically in neurons and immortalized cells, and therefore might diverge in their ultimate outcome and function. While evidence suggests that parkin can translocate to mitochondria in neurons, the function and mechanism of mitophagy downstream of parkin recruitment in neurons remains to be clarified. Moreover, it is noteworthy that most work has focused on the downstream signaling events in parkin/PINK1 mitophagy, whereas the upstream signaling pathways remain comparatively poorly characterized. Identifying the upstream signaling mechanisms that trigger parkin/PINK1 mitophagy will help to explain the nature of the insults affecting mitochondrial function in PD, and a better understanding of these pathways in neurons will be the key in identifying new therapeutic targets in PD. Frontiers Media S.A. 2013-07-19 /pmc/articles/PMC3715719/ /pubmed/23882257 http://dx.doi.org/10.3389/fneur.2013.00100 Text en Copyright © 2013 Grenier, McLelland and Fon. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc. |
spellingShingle | Neuroscience Grenier, Karl McLelland, Gian-Luca Fon, Edward A. Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? |
title | Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? |
title_full | Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? |
title_fullStr | Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? |
title_full_unstemmed | Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? |
title_short | Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? |
title_sort | parkin- and pink1-dependent mitophagy in neurons: will the real pathway please stand up? |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715719/ https://www.ncbi.nlm.nih.gov/pubmed/23882257 http://dx.doi.org/10.3389/fneur.2013.00100 |
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