Analysis of every type of cataract lenses show that there is an increased proteolysis and protein aggregation in them compared to age-matched controls. We have shown that truncated form of acylpeptide hydrolase(APH), similar to that present in vivo has protease activity and the ability to cleave alpha- and beta-crystallins. In vivo role of the truncated APH in proteolysis, crystallin aggregation or cataractogenesis is not known. The crystallin aggregates accumulating in vivo during aging contain C-terminally truncated alphaA- and alphaB-crystallins but it is yet to be established whether lens proteases action contributes to C-terminal truncation and whether C-terminal truncated crystallin is a causative factor in aggregation. Since short-range order interaction between crystallins has been implicated in maintenance of lens transparency we hypothesize that interactions of crystallin fragments (which are present in aged and cataract lenses) with lens proteins is likely to play a role in the development of lens opacity. Therefore we propose the following specific aims for our study to understand the role of proteases and crystallin fragments in protein aggregation in vivo.
The specific aims are: 1. a) Investigate the interaction of oxidized crystallin fragments during facilitated aggregation of betaL-and gamma-crystallins. b) Continue the studies on the low molecular weight crystallin fragments from human lenses by investigating their origin and properties including interaction with purified alpha-, beta- and gamma-crystallins. 2. Study the role of C-terminal truncation of alphaA- and alphaB-crystallin in high molecular weight aggregate formation and insolubilization. 3. a) Fully characterize the lens protease that has affinity to ATP and determine its role in crystallin truncation in vivo. b) Study the role of APH and its truncated form in crystallin degradation and cataractogenesis in transgenic mice.
| Schneck, Marilyn E; Lott, Lori A; Haegerstrom-Portnoy, Gunilla et al. (2012) Association between hearing and vision impairments in older adults. Ophthalmic Physiol Opt 32:45-52 |
| Sharma, K Krishna; Santhoshkumar, Puttur (2009) Lens aging: effects of crystallins. Biochim Biophys Acta 1790:1095-108 |
