Oh, Jeonghyun Catherine, Christy Kim, Eun Seon Min, Kwang Wook Jeong, Hae Chan Kim, Hyojin Kim, Mijin Ahn, Seung Hae Lukianenko, Nataliia Jo, Min Gu Bak, Hyeon Seok Lim, Sungsu Kim, Yun Kyung Kim, Ho Min Lee, Sung Bae Cho, Hyunju 2025-03-19T15:00:47Z 2025-03-19T15:00:47Z 2025-03-19 2025-01 https://pubs.kist.re.kr/handle/201004/151900 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. English Nature Publishing Group Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin Article 10.1038/s41467-025-56030-6 1 Nature Communications, v.16, no.1 Nature Communications 16 1 Y scie scopus 001399010500024 2-s2.0-85216192816 Multidisciplinary Sciences Science & Technology - Other Topics Article POLYGLUTAMINE AGGREGATION DISEASE TDP-43 PHOSPHORYLATION PEX19P POLYQ RECEPTOR COMPLEX DNAJB6 RNA-BINDING