Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease
Alpha-Synuclein (α-Syn) is a central protein in the pathogenesis of synucleinopathies, a group of neurodegenerative disorders including Parkinson’s disease (PD). Although its role in neurotransmission is well established, the precise role of this protein in disease pathogenesis is still not fully un...
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.578993/full |
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| author | Valentina Gilmozzi Giovanna Gentile Maria Paulina Castelo Rueda Andrew A. Hicks Peter P. Pramstaller Peter P. Pramstaller Alessandra Zanon Martin Lévesque Irene Pichler |
| author_facet | Valentina Gilmozzi Giovanna Gentile Maria Paulina Castelo Rueda Andrew A. Hicks Peter P. Pramstaller Peter P. Pramstaller Alessandra Zanon Martin Lévesque Irene Pichler |
| author_sort | Valentina Gilmozzi |
| collection | DOAJ |
| description | Alpha-Synuclein (α-Syn) is a central protein in the pathogenesis of synucleinopathies, a group of neurodegenerative disorders including Parkinson’s disease (PD). Although its role in neurotransmission is well established, the precise role of this protein in disease pathogenesis is still not fully understood. It is, however, widely regarded to be associated with the misfolding and accumulation of toxic intracellular aggregates. In fact, α-Syn is the most abundant protein component of Lewy bodies and Lewy neurites, which are also characterized by a high lipid content. Lipids, the main constituents of cellular membranes, have been implicated in many aspects of PD-related processes. α-Syn interacts with membrane phospholipids and free fatty acids via its N-terminal domain, and altered lipid-protein complexes might enhance both its binding to synaptic and mitochondrial membranes and its oligomerization. Several studies have highlighted a specific interaction of α-Syn with the phospholipid cardiolipin (CL), a major constituent of mitochondrial membranes. By interacting with CL, α-Syn is able to disrupt mitochondrial membrane integrity, leading to mitochondrial dysfunction. Additionally, externalized CL is able to facilitate the refolding of toxic α-Syn species at the outer mitochondrial membrane. In this review, we discuss how α-Syn/lipid interactions, in particular the α-Syn/CL interaction at the mitochondrial membrane, may affect α-Syn aggregation and mitochondrial dysfunction and may thus represent an important mechanism in the pathogenesis of PD. |
| first_indexed | 2024-12-13T06:13:14Z |
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| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-13T06:13:14Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-4d5d89c7d8694bd98ef5ff0c99d5bfea2022-12-21T23:57:02ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-10-011410.3389/fnins.2020.578993578993Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s DiseaseValentina Gilmozzi0Giovanna Gentile1Maria Paulina Castelo Rueda2Andrew A. Hicks3Peter P. Pramstaller4Peter P. Pramstaller5Alessandra Zanon6Martin Lévesque7Irene Pichler8Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyDepartment of Neurology, University of Lübeck, Lübeck, GermanyInstitute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyDepartment of Psychiatry and Neurosciences, Cervo Brain Research Centre, Université Laval, Quebec, QC,CanadaInstitute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, ItalyAlpha-Synuclein (α-Syn) is a central protein in the pathogenesis of synucleinopathies, a group of neurodegenerative disorders including Parkinson’s disease (PD). Although its role in neurotransmission is well established, the precise role of this protein in disease pathogenesis is still not fully understood. It is, however, widely regarded to be associated with the misfolding and accumulation of toxic intracellular aggregates. In fact, α-Syn is the most abundant protein component of Lewy bodies and Lewy neurites, which are also characterized by a high lipid content. Lipids, the main constituents of cellular membranes, have been implicated in many aspects of PD-related processes. α-Syn interacts with membrane phospholipids and free fatty acids via its N-terminal domain, and altered lipid-protein complexes might enhance both its binding to synaptic and mitochondrial membranes and its oligomerization. Several studies have highlighted a specific interaction of α-Syn with the phospholipid cardiolipin (CL), a major constituent of mitochondrial membranes. By interacting with CL, α-Syn is able to disrupt mitochondrial membrane integrity, leading to mitochondrial dysfunction. Additionally, externalized CL is able to facilitate the refolding of toxic α-Syn species at the outer mitochondrial membrane. In this review, we discuss how α-Syn/lipid interactions, in particular the α-Syn/CL interaction at the mitochondrial membrane, may affect α-Syn aggregation and mitochondrial dysfunction and may thus represent an important mechanism in the pathogenesis of PD.https://www.frontiersin.org/article/10.3389/fnins.2020.578993/fullalpha-synucleinParkinson’s diseaselipidscardiolipinaggregation |
| spellingShingle | Valentina Gilmozzi Giovanna Gentile Maria Paulina Castelo Rueda Andrew A. Hicks Peter P. Pramstaller Peter P. Pramstaller Alessandra Zanon Martin Lévesque Irene Pichler Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease Frontiers in Neuroscience alpha-synuclein Parkinson’s disease lipids cardiolipin aggregation |
| title | Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease |
| title_full | Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease |
| title_fullStr | Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease |
| title_full_unstemmed | Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease |
| title_short | Interaction of Alpha-Synuclein With Lipids: Mitochondrial Cardiolipin as a Critical Player in the Pathogenesis of Parkinson’s Disease |
| title_sort | interaction of alpha synuclein with lipids mitochondrial cardiolipin as a critical player in the pathogenesis of parkinson s disease |
| topic | alpha-synuclein Parkinson’s disease lipids cardiolipin aggregation |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.578993/full |
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