α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword
α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Alzheimer’s Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. In...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/4/507 |
| _version_ | 1827621657578045440 |
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| author | Li Yang Tan Kwan Hou Tang Lynette Yu You Lim Jia Xin Ong Hyokeun Park Sangyong Jung |
| author_facet | Li Yang Tan Kwan Hou Tang Lynette Yu You Lim Jia Xin Ong Hyokeun Park Sangyong Jung |
| author_sort | Li Yang Tan |
| collection | DOAJ |
| description | α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Alzheimer’s Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood–brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain. |
| first_indexed | 2024-03-09T11:07:27Z |
| format | Article |
| id | doaj.art-bcf2b38e3fbb4a8eb053fcf739365114 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T11:07:27Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-bcf2b38e3fbb4a8eb053fcf7393651142023-12-01T00:55:32ZengMDPI AGBiomolecules2218-273X2022-03-0112450710.3390/biom12040507α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged SwordLi Yang Tan0Kwan Hou Tang1Lynette Yu You Lim2Jia Xin Ong3Hyokeun Park4Sangyong Jung5Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138667, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138667, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138667, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138667, SingaporeDivision of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong KongInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138667, Singaporeα-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Alzheimer’s Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood–brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.https://www.mdpi.com/2218-273X/12/4/507α-synucleinParkinson’s diseaseLewy bodies (LB)dementia with Lewy bodiessynucleinopathypresynaptic axon terminal |
| spellingShingle | Li Yang Tan Kwan Hou Tang Lynette Yu You Lim Jia Xin Ong Hyokeun Park Sangyong Jung α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword Biomolecules α-synuclein Parkinson’s disease Lewy bodies (LB) dementia with Lewy bodies synucleinopathy presynaptic axon terminal |
| title | α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword |
| title_full | α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword |
| title_fullStr | α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword |
| title_full_unstemmed | α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword |
| title_short | α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword |
| title_sort | α synuclein at the presynaptic axon terminal as a double edged sword |
| topic | α-synuclein Parkinson’s disease Lewy bodies (LB) dementia with Lewy bodies synucleinopathy presynaptic axon terminal |
| url | https://www.mdpi.com/2218-273X/12/4/507 |
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