|ZFIN ID: ZDB-PUB-181127-84|
Transgenic zebrafish models reveal distinct molecular mechanisms for cataract-linked αA-crystallin mutants
Wu, S.Y., Zou, P., Mishra, S., Mchaourab, H.S.
|Source:||PLoS One 13: e0207540 (Journal)|
|Registered Authors:||Mchaourab, Hassane, Wu, Shu-Yu (Simon)|
|PubMed:||30475834 Full text @ PLoS One|
Wu, S.Y., Zou, P., Mishra, S., Mchaourab, H.S. (2018) Transgenic zebrafish models reveal distinct molecular mechanisms for cataract-linked αA-crystallin mutants. PLoS One. 13:e0207540.
ABSTRACTMutations in the small heat shock proteins α-crystallins have been linked to autosomal dominant cataracts in humans. Extensive studies in vitro have revealed a spectrum of alterations to the structure and function of these proteins including shifts in the size of the oligomer, modulation of subunit exchange and modification of their affinity to client proteins. Although mouse models of these mutants were instrumental in identifying changes in cellular proliferation and lens development, a direct comparative analysis of their effects on lens proteostasis has not been performed. Here, we have transgenically expressed cataract-linked mutants of αA- and αB-crystallin in the zebrafish lens to dissect the underlying molecular changes that contribute to the loss of lens optical properties. Zebrafish lines expressing these mutants displayed a range of morphological lens defects. Phenotype penetrance and severity were dependent on the mutation even in fish lines lacking endogenous α-crystallin. The mechanistic origins of these differences were investigated by the transgenic co-expression of a destabilized human γD-crystallin mutant. We found that the R49C but not the R116C mutant of αA-crystallin drove aggregation of γD-crystallin, although both mutants have similar affinity to client proteins in vitro. Our working model attributes these differences to the propensity of R49C, located in the buried N-terminal domain of αA-crystallin, to disulfide crosslinking as previously demonstrated in vitro. Our findings complement and extend previous work in mouse models and emphasize the need of investigating chaperone/client protein interactions in appropriate cellular context.