bi9b00739_si_001.pdf (1.39 MB)
Lipid Membranes Influence the Ability of Small Molecules To Inhibit Huntingtin Fibrillization
journal contribution
posted on 2019-10-17, 01:29 authored by Maryssa Beasley, Alyssa R. Stonebraker, Iraj Hasan, Kathryn L. Kapp, Barry J. Liang, Garima Agarwal, Sharon Groover, Faezeh Sedighi, Justin LegleiterSeveral
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.