Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin
Abstract Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington’s disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, we engineer the ATP-inde...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56030-6 |
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| author | Jeonghyun Oh Christy Catherine Eun Seon Kim Kwang Wook Min Hae Chan Jeong Hyojin Kim Mijin Kim Seung Hae Ahn Nataliia Lukianenko Min Gu Jo Hyeon Seok Bak Sungsu Lim Yun Kyung Kim Ho Min Kim Sung Bae Lee Hyunju Cho |
| author_facet | Jeonghyun Oh Christy Catherine Eun Seon Kim Kwang Wook Min Hae Chan Jeong Hyojin Kim Mijin Kim Seung Hae Ahn Nataliia Lukianenko Min Gu Jo Hyeon Seok Bak Sungsu Lim Yun Kyung Kim Ho Min Kim Sung Bae Lee Hyunju Cho |
| author_sort | Jeonghyun Oh |
| collection | DOAJ |
| description | Abstract Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington’s disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, we engineer the ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, we identify two yeast PEX19 variants and engineer equivalent mutations into human PEX19 (hsPEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of hsPEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hsPEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila. Overall, our data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD. |
| format | Article |
| id | doaj-art-ab910034761945429177c79a0edaee2c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ab910034761945429177c79a0edaee2c2025-01-19T12:30:51ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-025-56030-6Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtinJeonghyun Oh0Christy Catherine1Eun Seon Kim2Kwang Wook Min3Hae Chan Jeong4Hyojin Kim5Mijin Kim6Seung Hae Ahn7Nataliia Lukianenko8Min Gu Jo9Hyeon Seok Bak10Sungsu Lim11Yun Kyung Kim12Ho Min Kim13Sung Bae Lee14Hyunju Cho15Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS)Abstract Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington’s disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, we engineer the ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, we identify two yeast PEX19 variants and engineer equivalent mutations into human PEX19 (hsPEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of hsPEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hsPEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila. Overall, our data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD.https://doi.org/10.1038/s41467-025-56030-6 |
| spellingShingle | Jeonghyun Oh Christy Catherine Eun Seon Kim Kwang Wook Min Hae Chan Jeong Hyojin Kim Mijin Kim Seung Hae Ahn Nataliia Lukianenko Min Gu Jo Hyeon Seok Bak Sungsu Lim Yun Kyung Kim Ho Min Kim Sung Bae Lee Hyunju Cho Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin Nature Communications |
| title | Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin |
| title_full | Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin |
| title_fullStr | Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin |
| title_full_unstemmed | Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin |
| title_short | Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin |
| title_sort | engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin |
| url | https://doi.org/10.1038/s41467-025-56030-6 |
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