Identifying mechanisms that detect and eliminate aneuploid cells

Age-related macular degeneration, glaucoma and cataract are major causes of vision loss and all three diseases are age-related. Each is associated with the accumulation of senescent cells in, respectively, the retinal pigmented epithelium, the retinal ganglion cells, and the lens epithelium, and mouse model studies indicate that senescent cells contribute to the occurrence and progression of these eye diseases. Senescent cells are abnormal cells that accumulate during aging, fail to divide and instead have disruptive effects on tissue function. Recent research indicates that senescent cells are aneuploid ie have chromosomal abnormalities. Aneuploid cells can be removed from developing tissues and preliminary data indicates that other cells recognize them based on imbalanced ribosomal protein gene dose. Genetic screens will be performed in fruitfly eyes to isolate gene mutations that act in normal cells to prevent their recognizing and eliminating aneuploid cells. Whole genome sequencing and mapping methods will be used to identify the genes affected by these mutations, which will provide insight into the molecular mechanisms of aneuploid cell recognition and removal. It is anticipated that these studies can help understand how senescent cells accumulate to cause age-related macular degeneration, glaucoma and cataract, and suggest approaches to reduce the incidence and progression of these eye disases.