Coordination of Anle138b to Silver Results in Selective Reduction of a C-Terminal Truncated α-Synuclein Protein and Increased Aggregate Size.
The paper shows that forming a silver(I) trimeric complex with Anle138b alters α-synuclein aggregation in PFF-treated cell cultures by selectively reducing a ~12.4 kDa C-terminal truncated α-synuclein species and increasing aggregate size/morphology relative to the parent compound.
What the AI sees
The paper shows that forming a silver(I) trimeric complex with Anle138b alters α-synuclein aggregation in PFF-treated cell cultures by selectively reducing a ~12.4 kDa C-terminal truncated α-synuclein species and increasing aggregate size/morphology relative to the parent compound.
Research significance
This indicates metal complexation can modulate Anle138b's effects on pathogenic α-synuclein species and offers a novel chemical tool to study C-terminal truncation–driven aggregation, but the finding is currently limited to in vitro models and has unclear therapeutic translatability due to…
Source abstract
Parkinson's disease (PD) is a prevalent age-related neurodegenerative syndrome, partially thought to be caused by a decrease in α-synuclein proteostasis. Anle138b = 5-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-1H-pyrazole (HL) is undergoing clinical trials as a promising mitigator of α-synuclein aggregation. Because complexation to metals is known to modulate the activity of several drugs, we have prepared and characterized: H2L(ClO4), [CuI(µ-L)]3, and [AgI(µ-L)]3. To better understand the bioviability of these compounds, we monitored their effects in a cell culture model of α-synuclein protein aggregation using human α-synuclein preformed fibrils (PFFs). Using two different anti-α-synuclein antibodies, our data suggest that [AgI(µ-L)]3 decreases a C-terminal truncated protein that is approximately 12.4 kDa, as well as increases the size and alters the shape of PFF-induced aggregates. This indicates that [AgI(µ-L)]3 impacts aggregation in a manner different from HL and may serve as a novel tool for studying C-terminal truncation-related aggregation chemistry.