T cell Immunity in a Rare Juvenile Form of Motor Neuron Disease

PROJECT SUMMARY Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron disease (MND). Several reports have highlighted a link between some disease-causing genes and the immune system. However, whether and how immune cells contribute to MND in specific forms of ALS is yet to be defined. Amyotrophic Lateral Sclerosis 4 (ALS4) is a rare and juvenile MND caused by mutations in the gene SENATAXIN (SETX), which encodes for a nuclear helicase ubiquitously expressed that our group identified as a transcriptional regulator of inflammatory response. By using a mouse model of ALS4, we found that the hematopoietic system contributes to the neurodegenerative process. Additionally, we discovered that CD8 T cells in the CNS and the peripheral blood of disease-affected mice and patients are aberrantly activated. Our goal is to define the role of CD8 T cells in disease initiation and progression. We will determine the function of disease-associated CD8 T cells by transfer and depletion experiments and immune-histological characterization in mice (Aim 1). We will assess molecular pathways of neuro-immune interactions during disease by network modeling of transcriptomic and correlation-structure analyses (Aim 2). Finally, we will validate the presence of activated CD8 T cells in mouse models and patients with other forms of ALS (Aim 3). Our contribution of results will provide a deeper knowledge of the of CD8 T cells in ALS and open potential avenues for their use as immune biomarkers disease progression and as novel therapeutic target.