α-synuclein aggregation inhibitory activity of the bromotyrosine derivatives aerothionin and aerophobin-2 from the subtropical marine sponge Aplysinella sp

The neuronal protein alpha-synuclein (alpha-syn) is one of the main constituents of intracellular amyloid aggregations found in the post-mortem brains of Parkinson's disease (PD) patients. Recently, we screened the MeOH extracts obtained from 300 sub-tropical marine invertebrates for alpha-syn binding activity using affinity MS and this resulted in the extract of the Verongida marine sponge Aplysinella sp. 1194, (QM G339263) displaying molecules that bind to the protein. The subsequent bioassay-guided separation of the Aplysinella sp. extract led to the isolation of the known bromotyrosine derivatives (+)-aerothionin (1) and (+)-aerophobin-2 (2). Both compounds bind to alpha-syn as detected by a MS affinity assay and inhibit alpha-syn aggregation in an assay that uses the fluorescence probe, thioflavin T, to detect aggregation. (+)-Aerothionin (1) was toxic to primary dopaminergic neurons at its expected alpha-syn aggregation inhibitory concentration and so could not be tested for inhibition of pSyn aggregates in this functional assay. (+)-Aerophobin-2 (2) was not toxic and shown to weakly inhibit pSyn aggregation in primary dopaminergic neurons at 10 mu M.

Automated summary

The extract of the Verongida marine sponge Aplysinella sp. was found to contain two compounds that bind to alpha-synuclein and inhibit its aggregation. While one of the compounds was toxic to neurons, the other compound showed weak inhibitory effects on aggregation.