A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin
Abstract Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the ce...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-11-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301120 |
| _version_ | 1827771019357585408 |
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| author | Caijuan Li Yingqi Lin Yizhi Chen Xichen Song Xiao Zheng Jiawei Li Jun He Xiusheng Chen Chunhui Huang Wei Wang Jianhao Wu Jiaxi Wu Jiale Gao Zhuchi Tu Xiao‐Jiang Li Sen Yan Shihua Li |
| author_facet | Caijuan Li Yingqi Lin Yizhi Chen Xichen Song Xiao Zheng Jiawei Li Jun He Xiusheng Chen Chunhui Huang Wei Wang Jianhao Wu Jiaxi Wu Jiale Gao Zhuchi Tu Xiao‐Jiang Li Sen Yan Shihua Li |
| author_sort | Caijuan Li |
| collection | DOAJ |
| description | Abstract Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock‐in (KI‐140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins. |
| first_indexed | 2024-03-11T12:47:45Z |
| format | Article |
| id | doaj.art-78c18d8cc59e4fcd9b2d013316f18d02 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T12:47:45Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-78c18d8cc59e4fcd9b2d013316f18d022023-11-04T08:56:52ZengWileyAdvanced Science2198-38442023-11-011031n/an/a10.1002/advs.202301120A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant HuntingtinCaijuan Li0Yingqi Lin1Yizhi Chen2Xichen Song3Xiao Zheng4Jiawei Li5Jun He6Xiusheng Chen7Chunhui Huang8Wei Wang9Jianhao Wu10Jiaxi Wu11Jiale Gao12Zhuchi Tu13Xiao‐Jiang Li14Sen Yan15Shihua Li16Guangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaInstitute of Laboratory Animal Science Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaGuangdong Key Laboratory of Non‐human Primate Research Key Laboratory of CNS Regeneration (Ministry of Education) GHM Institute of CNS Regeneration Jinan University Guangzhou 510632 ChinaAbstract Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock‐in (KI‐140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins.https://doi.org/10.1002/advs.202301120HD KI‐140Q miceintravenous injectionlysosomemini‐intrabodymutant huntingtinSM3 |
| spellingShingle | Caijuan Li Yingqi Lin Yizhi Chen Xichen Song Xiao Zheng Jiawei Li Jun He Xiusheng Chen Chunhui Huang Wei Wang Jianhao Wu Jiaxi Wu Jiale Gao Zhuchi Tu Xiao‐Jiang Li Sen Yan Shihua Li A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin Advanced Science HD KI‐140Q mice intravenous injection lysosome mini‐intrabody mutant huntingtin SM3 |
| title | A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin |
| title_full | A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin |
| title_fullStr | A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin |
| title_full_unstemmed | A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin |
| title_short | A Specific Mini‐Intrabody Mediates Lysosome Degradation of Mutant Huntingtin |
| title_sort | specific mini intrabody mediates lysosome degradation of mutant huntingtin |
| topic | HD KI‐140Q mice intravenous injection lysosome mini‐intrabody mutant huntingtin SM3 |
| url | https://doi.org/10.1002/advs.202301120 |
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