A native chemical chaperone in the human eye lens

Abstract

Cataract is 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; it has therefore evolved remarkable mechanisms to resist light-scattering protein aggregation for a lifetime. We now report that one such mechanism involves an unusually abundant lens metabolite, myo-inositol, suppressing aggregation of lens crystallins. We quantified aggregation suppression using our previously well-characterized in vitro aggregation assays of oxidation-mimicking human γD-crystallin variants and investigated myo-inositol'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 neither the native nor the unfolded state of the protein, nor the final aggregated state, but rather the rate-limiting bimolecular step on the aggregation pathway. Given recent metabolomic evidence that it is severely depleted in human cataractous lenses compared to age-matched controls, we suggest that maintaining or restoring healthy levels of myo-inositol in the lens may be a simple, safe, and globally accessible strategy to prevent or delay lens opacification due to age-onset cataract.

Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens

“…In mature lens fiber cells, ATP, GSH, myo-inositol, NADPH, and polyols are needed to preserve protein solubility and SRO and to protect against light scattering and opacity. Several publications summarize the importance of lens metabolism to the maintenance of protein solubility, stability, structure, symmetric microcirculation, and resist oxidative and osmotic stress (87,93,(249)(250)(251)(252)(253)(254)(255)(256)(257).…”

α-Crystallin chaperone mimetic drugs inhibit lens γ-crystallin aggregation: Potential role for cataract prevention

“…Several studies by others have reported the existence of small molecules that bind to γ-crystallins, including lanosterol ( 59 ), cochineal carmine ( 60 ), ortho-Vanilin ( 61 ), quercetin ( 62 ), hesperetin ( 63 ), and sodium citrate ( 64 ). Moreover, small molecules with either demonstrated potential anticataract properties involving antiaggregation activity against crystallins include rosemarinic acid ( 65 ), morin ( 66 , 67 ), 25-hydrocholesterol ( 68 ), epigallocatechin gallate ( 69 ), and myoinositol ( 70 ). Among these compounds, those that were included in the screen included epigallocatechin gallate, which improved aggregation, whereas morin, lanosterol, hesperetin, and carmine had no impact.…”