Parkinson’s Disease-linked protein α-synuclein: do small-molecule inhibitors of protein aggregation also prevent its accumulation with lipids?

Parkinson’s Disease (PD), a neurodegenerative disorder, is characterized by the pathological aggregation of α-synuclein (αS) into Lewy bodies, primarily composed of fibrillar and lipid/membrane-rich αS inclusions. Recent studies suggest that both fibrillar and lipid-rich αS aggregates may contribute to PD pathology. This study investigates how lipid-rich αS inclusions are affected by small molecules that had previously been shown to disaggregate fibrillar αS protein aggregation. Using a live-cellular assay based on YFP-tagged membrane - accumulating, engineered αS-3K (E35K+E46K+E61K) in M17D neuroblastoma cells, we assessed the effects of fasudil, Epigallocatechin gallate (EGCG), anle138b, and ethanol compared to the positive control trifluoperazine (TFP), which is known to disassemble lipid-rich αS aggregates. fasudil, EGCG, and anle138b had previously been shown to prevent protein aggregation of αS. In our experiments, fasudil and anle138b significantly decreased inclusion formation in a dose - dependent manner in both αS lipid-rich inclusion prevention and reduction assays, while EGCG and ethanol exhibited either negligible or inclusion-increasing effects. These findings indicate that fasudil and anle138b may effectively target lipid-rich αS inclusions, supporting further exploration of their therapeutic potential in PD. However, fasudil’s observed associated toxicity necessitates careful evaluation. This study underscores the therapeutic relevance of targeting diverse αS aggregate types in PD.