Imbalances in the eye lens proteome are linked to cataract formation.

Nature structural & molecular biology 2021 Feb

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The prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The α-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in α-, β-, or γ-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the α-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins.

Citation

Philipp W N Schmid, Nicole C H Lim, Carsten Peters, Katrin C Back, Benjamin Bourgeois, Franz Pirolt, Bettina Richter, Jirka Peschek, Oliver Puk, Oana V Amarie, Claudia Dalke, Martin Haslbeck, Sevil Weinkauf, Tobias Madl, Jochen Graw, Johannes Buchner. Imbalances in the eye lens proteome are linked to cataract formation. Nature structural & molecular biology. 2021 Feb;28(2):143-151