Investigation and manipulation of photoreceptor proteostasis. (360G-Wellcome-092621_Z_10_Z)

Defects in protein homeostasis (proteostasis) are associated with neurodegeneration. In the retina, defects in proteostasis can lead to photoreceptor degeneration and blindness. There are currently no treatments for these conditions. This programme of work aims to i) map the photoreceptor response to protein misfolding and aggregation (proteostasis imbalance); ii) investigate the factors that mediate normal photoreceptor protein biogenesis and delineate the mechanisms of protein quality control and degradation; and iii) restore proteostasis in models of photoreceptor degeneration. We will concentrate on the two best characterized diseases associated with photoreceptor proteotoxicity, rhodopsin retinitis pigmentosa and SCA7 polyglutamine expansions. Through an integrated and multidisciplinary approach using cell and animal models we will probe the role of proteostasis networks in photoreceptor degeneration. Importantly, we will also manipulate the factors that facilitate protein folding and degradation to restore proteostasis. Such approaches could then be developed to combat these diseases. These studies may also have broader implications for other forms of photoreceptor degeneration and neurodegeneration in general.