Single-cell Transcriptomic and Genomic Analysis of Human Ataxia Telangiectasia Neurons

Key Words: Single-cell sequencing, neurodegeneration, ataxia telangiectasia, somatic mutation, cerebellum, Purkinje

Many forces can damage our DNA, including environmental forces like ultraviolet light, or internally generated mutagens like hydrogen peroxide and formaldehyde, which our cells produce in small quantities every day as natural byproducts of our metabolism. Because keeping the genome intact is vital to our survival, our cells have many mechanisms to sense DNA damage and fix it. When these mechanisms break down, it can cause disease. One such disease is Ataxia-telangiectasia (AT), a childhood neurodegenerative diseases caused by inherited mutations in a gene called ATM. ATM is a critical member of the DNA damage response in normal cells, but patients with AT lack functional ATM, leaving their genome vulnerable to damage. The result is that AT patients experience various deficits across their bodies, including the progressive shrinking of an area of the brain called the cerebellum, which is involved in movement. AT patients develop seemingly normally in early childhood, but by school age begin to show symptoms of loss of motor control, including difficulty walking and fine motor skill defects. AT progresses through adolescence, resulting in most patients relying on wheelchairs to get around. Some treatments exist to help control AT symptoms, but there are no treatments to slow brain degeneration in AT, and there is currently no cure. Until recently, technological limitations have made studying DNA damage in cells of the brain nearly impossible, so the types of damage that occur in AT-patient brains are unknown. Our lab and our collaborators have developed new high-resolution techniques to study the genome of individual cells of the human brain. In this proposal, we aim to apply those techniques to AT-patient brain samples to quantify and characterize damage to the genome in AT brain cells. We believe developing a molecular understanding of AT may be a step towards developing effective treatments for this disease.