Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin

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 () and Hyunju Cho ()
Additional contact information
Jeonghyun Oh: Institute for Basic Science (IBS)
Christy Catherine: Institute for Basic Science (IBS)
Eun Seon Kim: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Kwang Wook Min: Institute for Basic Science (IBS)
Hae Chan Jeong: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Hyojin Kim: Institute for Basic Science (IBS)
Mijin Kim: Institute for Basic Science (IBS)
Seung Hae Ahn: Institute for Basic Science (IBS)
Nataliia Lukianenko: Korea Institute of Science and Technology (KIST)
Min Gu Jo: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Hyeon Seok Bak: Institute for Basic Science (IBS)
Sungsu Lim: Korea Institute of Science and Technology (KIST)
Yun Kyung Kim: Korea Institute of Science and Technology (KIST)
Ho Min Kim: Institute for Basic Science (IBS)
Sung Bae Lee: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Hyunju Cho: Institute for Basic Science (IBS)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56030-6

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