The Role of folding of Actin in the retinal disease called Leber Congenital Amaurosis

What is it about?

When light rays enter our eye, they are focused by the cornea and lens onto the retina. The retina is a thin layer of tissue that consists of millions of tiny nerve cells that can detect the light. These nerve cells convert the light rays into electrical impulses, that are sent to the brain to produce the image. Leber congenital amaurosis (LCA) is a group of inherited retinal diseases that are the most common cause of blindness in newborn children. LCA accounts for approximately 5% of all inherited retinal disorders and affects between 1:30,000 to 1:81,000 individuals. Clinical observations of LCA patients are heterogeneous, including sensitivity to light (photophobia), involuntary eye movements (nystagmus), extreme farsightedness and usually almost to complete blindness. To date, no resolutive cure has been developed and disease treatment is symptomatic only. Actin and tubulin are two essential proteins for the retina that become functional through the folding machinery called TRiC, which has been associated with LCA. Actin forms the cytoskeleton that gives cells its shape, and tubulin stabilises the axons of nerve cells. TRiC consists of 8 subunits (Cct1 to Cct8) and loss of a single subunit leads to loss of the entire complex, which in turn results in loss of actin and tubulin function that cause severe LCA. I discovered a zebrafish mutant that carries a unique missense mutation in the Cct5 subunit, which assembles into mutant TRiC that folds tubulin, but not actin. In Cct5 mutants, the retina is largely intact. However, cell death (apoptosis) and pathological protein aggregation within the smaller mutant retina were detected. Additionally, specifically the cell numbers of the amacrine and the retinal ganglion cells were depleted, suggesting that the cct5-mutant retina was not uniformly affected by the reduced actin folding.

Featured Image

Photo by Colin Lloyd on Unsplash

Photo by Colin Lloyd on Unsplash

Why is it important?

Whereas the current literature suggests that LCA is predominantly affecting retinal photoreceptor cells and the retinal pigment epithelium, our analyses of the zebrafish cct5 mutant demonstrated the important role of folding of actin by the folding machine called TRiC.

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