Retinal dystrophy is a major cause of blindness worldwide. Recent molecular studies have suggested that protein folding and molecular chaperones might play a major role in the pathogenesis of these degenerations. Incorrect protein folding could be a common consequence of causative mutations in retinal degeneration disease genes, particularly mutations in the visual pigment rhodopsin. Furthermore several retinal degeneration disease genes have recently been identified as putative facilitators of correct protein folding, molecular chaperones on the basis of sequence homology. Disruption of proteostasis is a key event in many neurodegenerative diseases. Heat Shock Proteins (HSPs) participate in multiple functions associated with intracellular transport and proteostasis. Heat Shock Protein 90 (HSP90) is an abundant molecular chaperone with two isoforms, HSP90α and HSP90β. HSP90α was exclusively expressed in the retina, its deficiency caused retinitis pigmentosa (RP), a disease leading to blindness. HSP90α deficiency increased degradation of MAP1B by inducing its ubiquitination, causing α-tubulin deacetylation and microtubule destabilization. HSP90α was vital in maintaining rod PDE6 and AIPL1 cochaperone levels in rod photoreceptor cells. In cooperation with HSP90 and a photoreceptor specific co-chaperone AIPL1, HSP70 is implicated in facilitating correct folding and assembly of retinal cGMP phosphodiesterase (PDE6) holoenzyme. The different isoforms of HSP90, including the cytosolic HSP90 , the mitochondrial TRAP1, and the ER-specific GRP94, are involved in the different proteostatic mechanisms of photoreceptors, and elaborates on HSP90 function when retinal homeostasis is disturbed . The chaperone activity of YC-001 is evidenced by its ability to rescue the transport of multiple rhodopsin mutants in mammalian cells. YC-001 is also an inverse agonist that non-competitively antagonizes rhodopsin signaling. α-Crystallins are small heat-shock proteins that act as holdase chaperones . In humans, αA-crystallin is expressed only in the eye lens. αCrystallin chaperone activity can be compromised by mutation or posttranslational modifications, leading to protein aggregation and cataract.
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