A potential cause of
neurodegenerative diseases, including
Parkinson's disease (PD), is
protein misfolding and aggregation that in turn leads to neurotoxicity. Targeting Hsp90 is an attractive strategy to halt
neurodegenerative diseases, and
benzoquinone ansamycin (BQA) Hsp90 inhibitors such as
geldanamycin (GA) and
17-(allylamino)-17-demethoxygeldanamycin have been shown to be beneficial in mutant A53T α-
synuclein PD models. However, current BQA inhibitors result in off-target toxicities via redox cycling and/or arylation of nucleophiles at the C19 position. We developed novel 19-substituted BQA (19BQA) as a means to prevent arylation. In this study, our data demonstrated that 19-phenyl-GA, a lead 19BQA in the GA series, was redox stable and exhibited little toxicity relative to its parent
quinone GA in human dopaminergic SH-SY5Y cells as examined by oxygen consumption,
trypan blue, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium
bromide (MTT), and apoptosis assays. Meanwhile, 19-phenyl-GA retained the ability to induce autophagy and potentially protective
heat shock proteins (HSPs) such as Hsp70 and Hsp27. We found that transduction of A53T, but not wild type (WT) α-
synuclein, induced toxicity in SH-SY5Y cells. 19-Phenyl-GA decreased oligomer formation and toxicity of A53T α-
synuclein in transduced cells. Mechanistic studies indicated that
mammalian target of rapamycin (mTOR)/p70 ribosomal
S6 kinase signaling was activated by A53T but not WT α-
synuclein, and 19-phenyl-GA decreased mTOR activation that may be associated with A53T α-
synuclein toxicity. In summary, our results indicate that 19BQAs such as 19-phenyl-GA may provide a means to modulate
protein-handling systems including HSPs and autophagy, thereby reducing the aggregation and toxicity of
proteins such as mutant A53T α-
synuclein.