| Autor: |
Beasley M; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Stonebraker AR; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Hasan I; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Kapp KL; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Liang BJ; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Agarwal G; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Groover S; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Sedighi F; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States., Legleiter J; The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States.; Rockefeller Neurosciences Institute , West Virginia University , 1 Medical Center Drive , P.O. Box 9303, Morgantown , West Virginia 26505 , United States.; Department of Neuroscience , West Virginia University , 1 Medical Center Drive , P.O. Box 9303, Morgantown , West Virginia 26505 , United States. |
| Abstrakt: |
Several diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease (HD), are associated with specific proteins aggregating and depositing within tissues and/or cellular compartments. The aggregation of these proteins is characterized by the formation of extended, β-sheet rich fibrils, termed amyloid. In addition, a variety of other aggregate species also form, including oligomers and protofibrils. Specifically, HD is caused by the aggregation of the huntingtin (htt) protein that contains an expanded polyglutamine domain. Due to the link between protein aggregation and disease, small molecule aggregation inhibitors have been pursued as potential therapeutic agents. Two such small molecules are epigallocatechin 3-gallate (EGCG) and curcumin, both of which inhibit the fibril formation of several amyloid-forming proteins. However, amyloid formation is a complex process that is strongly influenced by the protein's environment, leading to distinct aggregation pathways. Thus, changes in the protein's environment may alter the effectiveness of aggregation inhibitors. A well-known modulator of amyloid formation is lipid membranes. Here, we investigated if the presence of lipid vesicles altered the ability of EGCG or curcumin to modulate htt aggregation and influence the interaction of htt with lipid membranes. The presence of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine or total brain lipid extract vesicles prevented the curcumin from inhibiting htt fibril formation. In contrast, EGCG's inhibition of htt fibril formation persisted in the presence of lipids. Collectively, these results highlight the complexity of htt aggregation and demonstrate that the presence of lipid membranes is a key modifier of the ability of small molecules to inhibit htt fibril formation. |
