Matches in SemOpenAlex for { <https://semopenalex.org/work/W4376647777> ?p ?o ?g. }
Showing items 1 to 59 of
59
with 100 items per page.
- W4376647777 abstract "As protein aggregation is the defining hallmark of all amyloid diseases, a common therapeutic strategy is to develop molecules that inhibit aggregation. However, this approach has yielded limited success. Many amyloid proteins directly interact with lipid membranes. These interactions promote distinct aggregation pathways and often result in membrane damage leading to toxicity. As a result, directly targeting the ability of amyloids to bind lipid membranes represents a novel therapeutic strategy. As a proof of principle, the interaction between lipid membranes and mutant huntingtin protein (htt) aggregates was used to test this strategy. Mutant htt containing an expanded polygulatmine (polyQ) domain causes Huntington’s disease (HD). Using a colorimetric lipid binding assay over 1200 compounds were screened for their ability to block htt/lipid binding. The screen was set up to only identify compounds that directly interacted with htt, not the lipid membrane. Three compounds were identified having the ability to inhibit htt/lipid interaction, Ro-90-7501 (Ro), benzamil hydrochloride (ben) and ruthenium red. As these compounds directly interact with htt, ThT and AFM assays were performed to assess their impact on aggregation. Ro and ben did not inhibit fibril formation; however, oligomer precursors were significantly smaller when exposed to Benzamil. Molecular dynamic simulations (MD) revealed that the two compounds have unique mechanisms of interaction with htt aggregates. Unlike Ro and ben, ruthenium red altered htt aggregation and inhibit fibrilization. Having established that the compound prevented htt from binding membranes, a C. elegans model of HD was used to determine if this strategy could alleviate phenotype. Despite have a minimal impact on punctate formation, all three compounds reduced a thrashing deficit in animals caused by mutant htt expression, suggesting that this strategy reduces htt toxicity." @default.
- W4376647777 created "2023-05-17" @default.
- W4376647777 creator A5018771818 @default.
- W4376647777 date "2023-05-16" @default.
- W4376647777 modified "2023-10-17" @default.
- W4376647777 title "Lipid binding properties of huntingtin as a novel therapeutic target" @default.
- W4376647777 doi "https://doi.org/10.33915/etd.11891" @default.
- W4376647777 hasPublicationYear "2023" @default.
- W4376647777 type Work @default.
- W4376647777 citedByCount "0" @default.
- W4376647777 crossrefType "dissertation" @default.
- W4376647777 hasAuthorship W4376647777A5018771818 @default.
- W4376647777 hasBestOaLocation W43766477771 @default.
- W4376647777 hasConcept C104317684 @default.
- W4376647777 hasConcept C11804247 @default.
- W4376647777 hasConcept C12554922 @default.
- W4376647777 hasConcept C136238340 @default.
- W4376647777 hasConcept C143065580 @default.
- W4376647777 hasConcept C179104552 @default.
- W4376647777 hasConcept C185592680 @default.
- W4376647777 hasConcept C2777633098 @default.
- W4376647777 hasConcept C2781427258 @default.
- W4376647777 hasConcept C39944091 @default.
- W4376647777 hasConcept C41625074 @default.
- W4376647777 hasConcept C55493867 @default.
- W4376647777 hasConcept C86803240 @default.
- W4376647777 hasConcept C95444343 @default.
- W4376647777 hasConceptScore W4376647777C104317684 @default.
- W4376647777 hasConceptScore W4376647777C11804247 @default.
- W4376647777 hasConceptScore W4376647777C12554922 @default.
- W4376647777 hasConceptScore W4376647777C136238340 @default.
- W4376647777 hasConceptScore W4376647777C143065580 @default.
- W4376647777 hasConceptScore W4376647777C179104552 @default.
- W4376647777 hasConceptScore W4376647777C185592680 @default.
- W4376647777 hasConceptScore W4376647777C2777633098 @default.
- W4376647777 hasConceptScore W4376647777C2781427258 @default.
- W4376647777 hasConceptScore W4376647777C39944091 @default.
- W4376647777 hasConceptScore W4376647777C41625074 @default.
- W4376647777 hasConceptScore W4376647777C55493867 @default.
- W4376647777 hasConceptScore W4376647777C86803240 @default.
- W4376647777 hasConceptScore W4376647777C95444343 @default.
- W4376647777 hasLocation W43766477771 @default.
- W4376647777 hasLocation W43766477772 @default.
- W4376647777 hasLocation W43766477773 @default.
- W4376647777 hasOpenAccess W4376647777 @default.
- W4376647777 hasPrimaryLocation W43766477771 @default.
- W4376647777 hasRelatedWork W1983207543 @default.
- W4376647777 hasRelatedWork W1992097939 @default.
- W4376647777 hasRelatedWork W2011171070 @default.
- W4376647777 hasRelatedWork W2043830939 @default.
- W4376647777 hasRelatedWork W2061238000 @default.
- W4376647777 hasRelatedWork W2075517262 @default.
- W4376647777 hasRelatedWork W2169210766 @default.
- W4376647777 hasRelatedWork W2317701649 @default.
- W4376647777 hasRelatedWork W3122934172 @default.
- W4376647777 hasRelatedWork W4283662003 @default.
- W4376647777 isParatext "false" @default.
- W4376647777 isRetracted "false" @default.
- W4376647777 workType "dissertation" @default.