CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease
Abstract Cereblon (CRBN) is a substrate recruiter for CRL4CRBN E3 ubiquitin ligase system playing a plethora of pivotal roles for biological systems. Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (α-SYN...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-10-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00801-3 |
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| author | Uroos Akber Jun-Hyung Jung Heewoong Yoon Jiwon Seo Chul-Seung Park |
| author_facet | Uroos Akber Jun-Hyung Jung Heewoong Yoon Jiwon Seo Chul-Seung Park |
| author_sort | Uroos Akber |
| collection | DOAJ |
| description | Abstract Cereblon (CRBN) is a substrate recruiter for CRL4CRBN E3 ubiquitin ligase system playing a plethora of pivotal roles for biological systems. Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (α-SYN) via modulation of DJ1. CRBN interferes with molecular activities of DJ1 in vitro, in cells, and in vivo resulting in a reduced disaggregation of α-SYN fibrils, increased formation of preformed fibrils (PFFs) of α-SYN, and high susceptibility of mice to MPTP and PFF-induced neurotoxicity. Depletion of Crbn improves the behavioral and biochemical responses of mice towards neurotoxic insult. Finally, we designed a peptide inhibitor to inhibit the recruitment of DJ1 to CRBN for ubiquitination, resulting in an enhanced supply of DJ1 to counteract the toxicity of aggregated α-SYN. Our data has important implications for development of CRBN-targeting therapies that could prevent or delay progression of neurodegenerative synucleinopathy. |
| format | Article |
| id | doaj-art-1ebdf84152bd4e569c2184a300d583a1 |
| institution | OA Journals |
| issn | 2373-8057 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-1ebdf84152bd4e569c2184a300d583a12025-08-20T02:11:25ZengNature Portfolionpj Parkinson's Disease2373-80572024-10-0110111410.1038/s41531-024-00801-3CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson diseaseUroos Akber0Jun-Hyung Jung1Heewoong Yoon2Jiwon Seo3Chul-Seung Park4Laboratory of Molecular Neurobiology, School of Life Sciences, Gwangju Institute of Science and Technology (GIST)Laboratory of Molecular Neurobiology, School of Life Sciences, Gwangju Institute of Science and Technology (GIST)Department of Chemistry, Peptide Drug Discovery Laboratory, Gwangju Institute of Science and Technology (GIST)Department of Chemistry, Peptide Drug Discovery Laboratory, Gwangju Institute of Science and Technology (GIST)Laboratory of Molecular Neurobiology, School of Life Sciences, Gwangju Institute of Science and Technology (GIST)Abstract Cereblon (CRBN) is a substrate recruiter for CRL4CRBN E3 ubiquitin ligase system playing a plethora of pivotal roles for biological systems. Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (α-SYN) via modulation of DJ1. CRBN interferes with molecular activities of DJ1 in vitro, in cells, and in vivo resulting in a reduced disaggregation of α-SYN fibrils, increased formation of preformed fibrils (PFFs) of α-SYN, and high susceptibility of mice to MPTP and PFF-induced neurotoxicity. Depletion of Crbn improves the behavioral and biochemical responses of mice towards neurotoxic insult. Finally, we designed a peptide inhibitor to inhibit the recruitment of DJ1 to CRBN for ubiquitination, resulting in an enhanced supply of DJ1 to counteract the toxicity of aggregated α-SYN. Our data has important implications for development of CRBN-targeting therapies that could prevent or delay progression of neurodegenerative synucleinopathy.https://doi.org/10.1038/s41531-024-00801-3 |
| spellingShingle | Uroos Akber Jun-Hyung Jung Heewoong Yoon Jiwon Seo Chul-Seung Park CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease npj Parkinson's Disease |
| title | CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease |
| title_full | CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease |
| title_fullStr | CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease |
| title_full_unstemmed | CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease |
| title_short | CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease |
| title_sort | crbn modulates synuclein fibrillation via degradation of dnajb1 in mouse model of parkinson disease |
| url | https://doi.org/10.1038/s41531-024-00801-3 |
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