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 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 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.

Copper Reductase Activity and Free Radical Chemistry by Cataract-Associated Human Lens γ-Crystallins

“…There is no treatment for cataracts beyond eye surgery, which is not risk-free and represents a high cost that amounts to billions of dollars per year. In developing countries, lack of access to cataract surgery makes this disease a major cause of visual disability …”

The Application of Quantitative Metabolomics for the Taxonomic Differentiation of Birds

“…Earlier in our lab, we found that the lenses of another nocturnal animal, the Rat ( R. norvegicus ), contain high concentrations of taurine, which prevails almost tenfold over myo -inositol (13.2 and 1.8 µmol/g correspondingly) [ 33 ]. It has been also recently suggested [ 48 ] that, besides osmotic protection, myo -inositol in the eye lens may act as a chaperone, protecting the lens proteins from the aggregation caused by post-translational modifications during a lifespan. Most likely, low levels of myo -inositol in owl lenses should be attributed to their nocturnal lifestyle, so the light-induced protein modifications for these species are less dangerous.…”

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 γcrystallins including lanosterol (61), cochineal carmine (62), orthovanilin (63), quercetin (64), hesperetin (65) and sodium citrate (66). Moreover, small molecules with either demonstrated or potential anticataract properties involving anti-aggregation activity against crystallins include rosemarinic acid (67), morin (68,69), 25-hydrocholesterol(70),EGCG (71) and myoinositol (72). Among these compounds, those that were included in the screen included EGCG, which improved aggregation, while morin, lanosterol, hesperetin and carmine had no impact.…”