Early Study Identifies at Least 6 Compounds That Might Prevent Alpha-Synuclein Clumping

Using a new screening strategy, researchers have identified compounds that block the clumping of alpha-synuclein protein, a key event in Parkinson’s.

The study, “Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State,” appeared in the journal Cell Chemical Biology.

Aggregated alpha-synuclein is the main component of Parkinson’s hallmark Lewy bodies. Screening of compounds that may prevent alpha-synuclein from clumping has been hampered by its slow and random aggregation pattern and the difficult detection of early-stage alpha-synuclein oligomers. These oligomers consist of a few units (or monomers) and are suggested to be the most toxic form of alpha-synuclein.

Researchers at Aarhus University, Denmark, developed a high-throughput screening assay using Förster Resonance Energy Transfer (FRET), a common technique for measuring tiny distances between molecules, close enough for molecular interactions to occur.

High-throughput screening is a method commonly used in drug discovery that uses robotics, data processing, and sensitive detectors — among other tools — to quickly conduct millions of chemical, genetic, or pharmacological tests.

“It is in our common [Parkinson’s]-combating interest to obtain as many leads as possible to maximize the likelihood of a successful [treatment] candidate,” the researchers wrote.

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The team first developed a way to make alpha-synuclein clump more rapidly and predictably by using sodium dodecyl sulfate (SDS), a widely used detergent molecule in chemical analysis and biotechnology.

The combination of SDS-induced aggregation with FRET enabled the screening of 746,000 compounds, 58 of which markedly inhibited early alpha-synuclein clumping and lessened oligomers-induced cell membrane interactions.

These identified inhibitors were structurally diverse. The six most effective were derivatives of the same molecule. All interacted strongly with the first portion of alpha-synuclein monomers, known as the N-terminal region. Proteins are composed of several amino acids and have two distinct regions: N-terminus, the start of the protein, and C-terminus, the end of its amino-acid chain.

Several compounds reduced the oligomers’ toxicity in nerve cells grown in laboratory dishes. Although the inhibitors introduced chemical modifications in clumped alpha-synuclein, these changes were not necessary for their beneficial (inhibitory) activity.

The team also discovered compounds that boosted the protein’s aggregation, or “proaggregators” that share the same structural core. The researchers suggested they may be useful to modulate and study alpha-synuclein clumping at the cellular level.

Overall, the new clumping inhibitors “have the potential to further elucidate the mechanisms underlying the pathophysiology of [alpha-synuclein]” in models such as stem cell-derived neurons from patients, “which will provide necessary insights for future therapies,” the researchers wrote.

While these findings are in the context of Parkinson’s, “this FRET-based assay can screen for compounds affecting the aggregation behavior of any protein,” they added.