Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation
α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screenin...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.561462/full |
| _version_ | 1818693343373164544 |
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| author | James H. Torpey Richard M. Meade Ravina Mistry Jody M. Mason Jillian Madine |
| author_facet | James H. Torpey Richard M. Meade Ravina Mistry Jody M. Mason Jillian Madine |
| author_sort | James H. Torpey |
| collection | DOAJ |
| description | α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxicity. We utilize NMR to probe association and identify that 4554W associates with a “partially aggregated” form of aSyn, with enhanced association occurring over time. We also report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale as aSyn aggregation in vitro, with peptide modification enhancing its association with aSyn. Additionally, we report that 4554W can act to reduce fibril formation of five Parkinson’s disease associated aSyn mutants. Inhibitory peptide binding to partially aggregated forms of aSyn, as identified here, is particularly attractive from a therapeutic perspective, as it would eliminate the need to administer the therapy at pre-aggregation stages, which are difficult to diagnose. Taken together the data suggest that 4554W could be a suitable candidate for future therapeutic development against wild-type, and most mutant aSyn aggregation. |
| first_indexed | 2024-12-17T13:12:10Z |
| format | Article |
| id | doaj.art-4b84b3dabe714962abc73dfd7706266d |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-17T13:12:10Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-4b84b3dabe714962abc73dfd7706266d2022-12-21T21:47:05ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-10-011410.3389/fnins.2020.561462561462Insights Into Peptide Inhibition of Alpha-Synuclein AggregationJames H. Torpey0Richard M. Meade1Ravina Mistry2Jody M. Mason3Jillian Madine4Institute of Integrative Biology, University of Liverpool, Liverpool, United KingdomDepartment of Biology and Biochemistry, University of Bath, Bath, United KingdomInstitute of Integrative Biology, University of Liverpool, Liverpool, United KingdomDepartment of Biology and Biochemistry, University of Bath, Bath, United KingdomInstitute of Integrative Biology, University of Liverpool, Liverpool, United Kingdomα-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxicity. We utilize NMR to probe association and identify that 4554W associates with a “partially aggregated” form of aSyn, with enhanced association occurring over time. We also report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale as aSyn aggregation in vitro, with peptide modification enhancing its association with aSyn. Additionally, we report that 4554W can act to reduce fibril formation of five Parkinson’s disease associated aSyn mutants. Inhibitory peptide binding to partially aggregated forms of aSyn, as identified here, is particularly attractive from a therapeutic perspective, as it would eliminate the need to administer the therapy at pre-aggregation stages, which are difficult to diagnose. Taken together the data suggest that 4554W could be a suitable candidate for future therapeutic development against wild-type, and most mutant aSyn aggregation.https://www.frontiersin.org/article/10.3389/fnins.2020.561462/fullalpha-synucleinelectron microscopyneurodegenerative diseaseNMRParkinson diseasepeptide interaction |
| spellingShingle | James H. Torpey Richard M. Meade Ravina Mistry Jody M. Mason Jillian Madine Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation Frontiers in Neuroscience alpha-synuclein electron microscopy neurodegenerative disease NMR Parkinson disease peptide interaction |
| title | Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation |
| title_full | Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation |
| title_fullStr | Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation |
| title_full_unstemmed | Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation |
| title_short | Insights Into Peptide Inhibition of Alpha-Synuclein Aggregation |
| title_sort | insights into peptide inhibition of alpha synuclein aggregation |
| topic | alpha-synuclein electron microscopy neurodegenerative disease NMR Parkinson disease peptide interaction |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.561462/full |
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