Asset Details
Do you wish to reserve the book?
Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin
Do you wish to request the book?
Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin
2025
Overview
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 (
hs
PEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of
hs
PEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the
hs
PEX19-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.
Toxic protein aggregation is a hallmark of various neurodegenerative diseases. Here, authors show that ATP-independent membrane protein chaperones can serve as a simple design platform for targeting proteotoxic aggregates linked to Huntington’s disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 82/29
/ 82/83
/ 96/63
/ Animals
/ Humanities and Social Sciences
/ Humans
/ Huntingtin Protein - genetics
/ Huntingtin Protein - metabolism
/ Huntington Disease - genetics
/ Huntington Disease - metabolism
/ Huntington Disease - pathology
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Molecular Chaperones - genetics
/ Molecular Chaperones - metabolism
/ Mutants
/ Mutation
/ Protein Aggregation, Pathological - genetics
/ Protein Engineering - methods
/ Proteins
/ Saccharomyces cerevisiae - genetics
/ Saccharomyces cerevisiae - metabolism
/ Saccharomyces cerevisiae Proteins - genetics
/ Saccharomyces cerevisiae Proteins - metabolism
/ Science
/ Toxicity
/ Yeast
