Towards a better understanding of the role of ataxin 7 in a rare genetic disease
In an immature retina, photoreceptors are made up of an external segment that is still very short. In a normal retina, the external segments of mature photoreceptors are damaged by light and must be continuously reformed. In the retina of SCA7 patients, the external segments are not reformed and become smaller and smaller and less and less functional
Dec. 4, 2018
Spinocerebellar ataxia type 7 or SCA7 is an inherited neurodegenerative disease due to an expansion of polyglutamine in a protein called ataxin 7. This type of disease usually occurs in adulthood and leads to the death of patients 10 to 20 years after apparition of the first symptoms. Currently, there is no therapy to counter the course of this disease. In this study, Yvon Trottier's team at the IGBMC (CNRS/Inserm/University of Strasbourg) showed that ataxin 7 plays an essential role in the morphogenesis of the vertebrate eye and in the differentiation of photoreceptors, the light-sensitive neurons located on the retina. They also observed that the loss of function of this protein could contribute to the development of the human coloboma, an abnormal development of the eye, which affects about one in 5000 births. Results published on November 16, 2018 in the journal Human Molecular Genetics.
People with spinocerebellar ataxia type 7 (SCA7) have their vision gradually and inevitably decreased to blindness, before more severe symptoms develop. This is due to a mutation in the gene encoding ataxin 7. In this study, Yvon Trottier's team sought to better understand the function of this protein.
In order to inactivate the gene encoding ataxin 7, researchers used antisense oligonucleotides, which target proteins before they can be expressed, as well as CRISPR-CAS9, a DNA modification technology. "We have observed that the inactivation of ataxin 7 in zebrafish leads to the overexpression of a molecular pathway called Sonic hedgehog," says Yvon Trottier. This overexpression leads to a characteristic malformation of the eye, called coloboma.
In addition to this eye development disorder, ataxin 7 deficiency induces poor development of retinal photoreceptors in zebrafish. Photoreceptors have a unique structure, called external segments, that allows them to capture light. "When ataxine-7 is inactivated, photoreceptors can no longer form their external segments," explains the researcher. "This information helps us understand why SCA7 patients lose their vision. In a normal retina, the outer segments of the photoreceptors are damaged by light and must be continuously reformed. In the retinas of SCA7 patients, the external segments are not reformed and become smaller and smaller and less functional." This suggests that the responsible mutation of SCA7 causes a loss of function of ataxin-7, which can no longer participate in the reformation of the external segments.
These results indicate that ataxin 7 plays an essential role in the eye development and in the photoreceptors differentiation and renewal. The loss of function of this protein could be involved in the formation of the human coloboma. It could therefore become a new strategic target for the treatment of eye diseases.