Osama Al Dalahmah, MD, PhD

Neuropathology Fellow, Jim Goldman, Columbia University

The Transcriptional Landscape of Huntington Disease; Exploring the Neuroprotective Potential of Astrocytes at The Single Cell Level

Huntington’s disease (HD) is caused by a genetic mutation in the huntingtin (HTT) gene. The mutation is present in all brain cells, including neurons and supportive cells called astrocytes. Astrocytes are the major non-neuronal cells in the brain and maintain a healthy environment around neurons. In HD, astrocytes may become dysfunctional, contributing to the death of neurons. We hypothesize that astrocytes have two roles: they can either have protective effects on neurons, or become dysfunctional and lose their protective effects. We will test whether there are more of these “helpful” astrocytes in early HD, and whether there are more of the “damaging” astrocytes in more advanced stages of HD. To distinguish between the helpful and damaging cells, we need to examine which genetic RNA messages are found in single astrocytes in the human brain. We are using a cutting-edge technique for the first time in human HD brain tissue that allows us to isolate the cell nuclei, where the genetic information is stored. We then take RNA from individual nuclei and sequence it, and this knowledge allows us to understand the biological processes that underlie protective versus destructive astrocytes. By investigating how astrocytes in the HD brain are changed during the course of the disease, we will be better able to develop targeted therapeutic strategies for overcoming and possibly reversing these deleterious changes.