Identifying Parkinson’s Inhibitors
Screening nearly 750,000 molecules for inhibitors of α-synuclein protein aggregation
Luke Turner | | Quick Read
Parkinson’s disease is the second most prevalent neurodegenerative disease and the most common movement disorder globally. Although its symptoms can be treated to an extent, there is currently no cure and no way to stop the progress of the disease. A major contributor to the onset of Parkinson’s disease is the aggregation of the natively unfolded protein α-synuclein (αSN), which forms both small oligomeric complexes and large fibrillary deposits. Attempts to identify compounds that inhibit this aggregation are hindered by its irregular and variable nature – but one research group may have found a better way (1). Daniel Otzen and his team stimulated αSN aggregation using sodium dodecyl sulfate (SDS) and then screened 746,000 compounds to identify the six most effective aggregation inhibitors using Fӧrster resonance energy transfer (FRET).
“We show that these compounds truly do prevent αSN aggregation,” says Otzen. “They just have the unfortunate side effect of also reacting chemically with αSN by forming covalent chemical bonds with it. Perhaps they can be modified to reduce their chemical reactivity while retaining their inhibitory role.”
All six compounds are derivatives of (4-hydroxynaphthalen-1-yl) sulfonamide that share a core structure. Otzen thinks that their inhibitory qualities stem from interactions with the N-terminal region of monomeric αSN. “We believe that by binding to the N-terminal region, the compounds prevent the formation of intermolecular αSN interactions that are otherwise required for the aggregation process to proceed to form oligomers. Furthermore, the compounds can also bind to pre-existing oligomers where the N-terminal part is partially exposed and neutralize its toxic, membrane-binding effects.”
Moving forward, Otzen wants to take the research in vivo and attempt to apply these findings on a practical level. “We would like to develop compounds that are truly specific to the αSN oligomer, so we can provide drugs for both diagnostics (early-stage detection of Parkinson’s disease) and therapy (by binding and neutralizing toxic species). Currently, we are not limiting ourselves to small molecules; we are also looking at peptides, which are easier to manipulate systematically, and antibodies, which tap into the amazing selection system of our immune system.”
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- Kurnik et al., “Potent α-synuclein aggregation inhibitors, identified by high-throughput screening, mainly target the monomeric state”, Cell Chem Biol, 25, 1–14 (2018). PMID: 30197194.