The relationship of alpha-synuclein to mitochondrial dynamics and quality control
The relationship of alpha-synuclein to mitochondrial dynamics and quality control
Maintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the mitochondrial network and effective mitochondrial quality control mechanisms including the mitochondrial-derived vesicle pathway and mitophagy. Mitochondrial dysfunction has been implicated in driving the pathology of several neurodegenerative diseases, including Parkinson’s disease (PD) where dopaminergic neurons in the substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions in organelle quality control, indicating that dysregulation in mitochondrial quality control may represent a key element of pathology. The most well-characterized aspect of PD pathology relates to alpha-synuclein; an aggregation-prone protein that forms intracellular Lewy-body inclusions. Details of how alpha-synuclein exerts its toxicity in PD is not completely known, however, dysfunctional mitochondria have been observed in both PD patients and models of alpha-synuclein pathology. Accordingly, an association between alpha-synuclein and mitochondrial function has been established. This relates to alpha-synuclein’s role in mitochondrial transport, dynamics, and quality control. Despite these relationships, there is limited research defining the direct mechanisms linking alpha-synuclein to mitochondrial dynamics and quality control. In this review, we will discuss the current literature addressing this association and provide insight into the proposed mechanisms promoting these functional relationships. We will also consider some of the alternative mechanisms linking alpha-synuclein with mitochondrial dynamics and speculate what the relationship between alpha-synuclein and mitochondria might mean both physiologically and in relation to PD.
Parkinson’s disease, lysosome, membrane trafficking, mitochondria, mitochondrial quality control, vesicle transport
Thorne, Naomi Jasmin
3a884c6f-8495-4137-b454-0bd942efa7a3
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
26 August 2022
Thorne, Naomi Jasmin
3a884c6f-8495-4137-b454-0bd942efa7a3
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Thorne, Naomi Jasmin and Tumbarello, David A.
(2022)
The relationship of alpha-synuclein to mitochondrial dynamics and quality control.
Frontiers in Molecular Neuroscience, 15, [947191].
(doi:10.3389/fnmol.2022.947191).
Abstract
Maintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the mitochondrial network and effective mitochondrial quality control mechanisms including the mitochondrial-derived vesicle pathway and mitophagy. Mitochondrial dysfunction has been implicated in driving the pathology of several neurodegenerative diseases, including Parkinson’s disease (PD) where dopaminergic neurons in the substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions in organelle quality control, indicating that dysregulation in mitochondrial quality control may represent a key element of pathology. The most well-characterized aspect of PD pathology relates to alpha-synuclein; an aggregation-prone protein that forms intracellular Lewy-body inclusions. Details of how alpha-synuclein exerts its toxicity in PD is not completely known, however, dysfunctional mitochondria have been observed in both PD patients and models of alpha-synuclein pathology. Accordingly, an association between alpha-synuclein and mitochondrial function has been established. This relates to alpha-synuclein’s role in mitochondrial transport, dynamics, and quality control. Despite these relationships, there is limited research defining the direct mechanisms linking alpha-synuclein to mitochondrial dynamics and quality control. In this review, we will discuss the current literature addressing this association and provide insight into the proposed mechanisms promoting these functional relationships. We will also consider some of the alternative mechanisms linking alpha-synuclein with mitochondrial dynamics and speculate what the relationship between alpha-synuclein and mitochondria might mean both physiologically and in relation to PD.
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Thorne and Tumbarello_Accepted version_Frontiers Mol Neurosci
- Accepted Manuscript
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fnmol-15-947191
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Accepted/In Press date: 2 August 2022
Published date: 26 August 2022
Additional Information:
Funding Information:
This work was supported by a Wellcome Trust Seed Award (205909/Z/17/Z) and a Gerald Kerkut Trust Ph.D. studentship to NT.
Publisher Copyright:
Copyright © 2022 Thorne and Tumbarello.
Keywords:
Parkinson’s disease, lysosome, membrane trafficking, mitochondria, mitochondrial quality control, vesicle transport
Identifiers
Local EPrints ID: 469680
URI: http://eprints.soton.ac.uk/id/eprint/469680
ISSN: 1662-5099
PURE UUID: 7dcb30f4-e6ba-4c00-806c-734e878dbd2d
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Date deposited: 22 Sep 2022 16:34
Last modified: 17 Mar 2024 04:03
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