Neurodegenerative diseases are caused by the loss of nerves from the brain and spinal cord. Almost all focus in the field has been on figuring out what goes wrong in neurons themselves, but growing evidence implicates the immune system as another key driver of these diseases. The immune system has evolved to fight off foreign invaders such as bacteria and viruses, but as we age or if we have genetic alterations, it seems to undergo changes that cause it to attack neurons in the brain. Combining expertise in neurodegenerative disease, genetics, immune cell biology, chemical biology, and protein engineering, this team aims to understand whether symptoms of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia result from immune cells attacking altered or dysfunctional neurons. Immune cells have already been successfully deployed to treat a wide range of cancers. In the second part of this proposal, the team aims to harness engineered immune cells as therapies for neurodegenerative diseases.