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- W4319931036 abstract "Light-scattering protein aggregates in the eye lens cause cataract, one of the most prevalent protein aggregation disorders and still the most common cause of vision loss worldwide. The metabolically quiescent core region of the human lens lacks cellular or protein turnover and has therefore evolved remarkable mechanisms to resist protein aggregation for a lifetime. Lens cytoplasm becomes progressively more oxidizing with age and especially with cataract onset. Proteomic and in vitro studies have converged on the importance of lens γ-crystallin misfolding via formation of non-native disulfide bonds for light scattering aggregation. We have now found that one of the evolved mechanisms of lens resilience involves an unusually abundant lens metabolite, myo-inositol, that suppresses oxidative γ-crystallin aggregation without being redox-active itself. We quantified aggregation suppression using our previously well-characterized in vitro aggregation assays of oxidation-mimicking human γD-crystallin variants and investigated myoinositol's molecular mechanism of action using solution NMR, negative-stain TEM, differential scanning fluorometry, thermal scanning Raman spectroscopy, turbidimetry in redox buffers, and free thiol quantitation. Unlike many known chemical chaperones, myo-inositol's primary target was not the native, unfolded, or final aggregated states of the protein; rather, we propose that it was the rate-limiting bimolecular step on the aggregation pathway. Given recent metabolomic evidence that myo-inositol is severely depleted in human cataractous lenses compared to age-matched controls, maintaining or restoring healthy levels of this compound in the lens may be a simple, safe, and globally accessible strategy to prevent or delay lens opacification due to age-onset cataract." @default.
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- W4319931036 date "2023-02-01" @default.
- W4319931036 modified "2023-09-25" @default.
- W4319931036 title "A native chemical chaperone in the human eye lens suppresses redox-dependent lens crystallin misfolding" @default.
- W4319931036 doi "https://doi.org/10.1016/j.bpj.2022.11.1879" @default.
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