Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ.
Misfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is c...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0165964&type=printable |
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| author | David C Butler Shubhada N Joshi Erwin De Genst Ankit S Baghel Christopher M Dobson Anne Messer |
| author_facet | David C Butler Shubhada N Joshi Erwin De Genst Ankit S Baghel Christopher M Dobson Anne Messer |
| author_sort | David C Butler |
| collection | DOAJ |
| description | Misfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is critical for initial aggregation. Using neuronal cell lines, we show that as a bifunctional nanobody fused to a proteasome targeting signal, VH14PEST can counteract heterologous proteostatic effects of mutant α-Syn on mutant huntingtin Exon1 and protect against α-Syn toxicity using propidium iodide or Annexin V readouts. We compared this anti-NAC candidate to NbSyn87, which binds to the C-terminus of α-Syn. NbSyn87PEST degrades α-Syn as well or better than VH14PEST. However, while both candidates reduced toxicity, VH14PEST appears more effective in both proteostatic stress and toxicity assays. These results show that the approach of reducing intracellular monomeric targets with novel antibody engineering technology should allow in vivo modulation of proteostatic pathologies. |
| format | Article |
| id | doaj-art-fda9170016e14126bcbaf644edb3fdcf |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-fda9170016e14126bcbaf644edb3fdcf2025-08-20T03:24:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-011111e016596410.1371/journal.pone.0165964Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ.David C ButlerShubhada N JoshiErwin De GenstAnkit S BaghelChristopher M DobsonAnne MesserMisfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is critical for initial aggregation. Using neuronal cell lines, we show that as a bifunctional nanobody fused to a proteasome targeting signal, VH14PEST can counteract heterologous proteostatic effects of mutant α-Syn on mutant huntingtin Exon1 and protect against α-Syn toxicity using propidium iodide or Annexin V readouts. We compared this anti-NAC candidate to NbSyn87, which binds to the C-terminus of α-Syn. NbSyn87PEST degrades α-Syn as well or better than VH14PEST. However, while both candidates reduced toxicity, VH14PEST appears more effective in both proteostatic stress and toxicity assays. These results show that the approach of reducing intracellular monomeric targets with novel antibody engineering technology should allow in vivo modulation of proteostatic pathologies.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0165964&type=printable |
| spellingShingle | David C Butler Shubhada N Joshi Erwin De Genst Ankit S Baghel Christopher M Dobson Anne Messer Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ. PLoS ONE |
| title | Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ. |
| title_full | Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ. |
| title_fullStr | Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ. |
| title_full_unstemmed | Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ. |
| title_short | Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ. |
| title_sort | bifunctional anti non amyloid component α synuclein nanobodies are protective in situ |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0165964&type=printable |
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