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- W4247945991 abstract "Aberrant protein folding is implicated in several devastating neurodegenerative diseases. Inclusions containing the proteins TDP-43 and FUS are implicated in some cases of amyotrophic lateral sclerosis (ALS), while amyloid fibers comprised of α-synuclein are implicated in Parkinson's disease. Hsp104, an AAA+ protein from yeast, functions in regulating the disassembly of amorphous aggregates as well as prions. There are no other proteins known that are capable of specifically disassembling and solubilizing amyloid. Though Hsp104 is highly conserved, it has no human homologue. Therefore, we have developed potentiated Hsp104 variants and applied them to disease models of TDP-43, FUS, and α-synuclein pathology. These potentiated Hsp104 variants dissolve the aggregates, return the proteins to their proper cellular location, and strongly suppress toxicity in each of these disease models at levels far greater than wild-type. Surprisingly, we have also found that at certain positions in Hsp104, generic mutations to nearly any class of amino acid yield a hyperactive protein capable of eliminating aggregates. using pure protein biochemistry experiments, we have probed the biochemical basis for these variants' potentiated activity and found that they have an enhanced ATPase and translocation rate, and are capable of dissolving aggregates without requiring co-chaperone collaboration. These results reveal important new insights into the mechanism by which Hsp104 dissolves amyloid, and demonstrate that proteins that misfold in neurodegenerative disease can be reactivated to their native state." @default.
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- W4247945991 date "2013-01-01" @default.
- W4247945991 modified "2023-09-26" @default.
- W4247945991 title "Potentiated Hsp104 Variants Antagonize Diverse Protein Misfolding Events" @default.
- W4247945991 doi "https://doi.org/10.1016/j.bpj.2012.11.3167" @default.
- W4247945991 hasPublicationYear "2013" @default.
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