Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils

Area of Science:

• Neuroscience
• Molecular Biology
• Drug Discovery

Background:

• Alpha-synuclein aggregation is central to Parkinson's disease (PD) and synucleinopathies.
• Targeting these protein aggregates is a key therapeutic strategy.

Purpose of the Study:

• To identify small molecules that can disassemble preformed alpha-synuclein fibrils.
• To evaluate the therapeutic potential of these molecules in disease models.

Main Methods:

• In vitro disaggregation assays using recombinant alpha-synuclein fibrils.
• Cellular assays to assess prevention of seeded aggregation and cytotoxicity.
• In vivo studies in *C. elegans* and brain penetration studies in mice.
• Molecular dynamics simulations to predict mechanism of action.

Main Results:

• CNS-11 and CNS-11g disaggregated recombinant alpha-synuclein fibrils in vitro.
• Compounds prevented intracellular seeded aggregation and reduced fibril cytotoxicity in neuronal cells.
• Disassembly of patient-derived MSA fibrils and reduced in vivo aggregates in *C. elegans* were observed.
• Compounds demonstrated brain tissue penetration in mice.

Conclusions:

• CNS-11 and CNS-11g are effective disaggregators of alpha-synuclein fibrils.
• These compounds show promise as therapeutic leads for synucleinopathies.
• Potential mechanism involves interaction with the N terminus of the fibril core.