Basic Biology

Dr. Jack Humphrey (Icahn School of Medicine at Mount Sinai, pictured left) and his collaborators are studying how immune cells in the nervous system track with and influence survival in ALS. Taking a unique approach, the team specifically set out to study differences in genes in the brain in high, medium, or slow disease progressors. They identified two immune markers, CHIT1 and C3, that strongly track with rapid disease progression. Their dataset provides key evidence to elevate these markers as candidate biomarkers for disease progression and potential therapeutic targets.

By analyzing brain and spinal cord tissue samples, Dr. Gate’s research found that neuroinflammation is higher in the spinal cord rather than the brain. Additionally, this signal is amplified in C9orf72 ALS relative to sporadic ALS. Specifically, immune cells in the brain called microglia showed the most striking gene changes, indicating that their protective function is impaired in ALS.

Dr. Amanda Guise (Biogen, pictured left) analyzed proteins within single cells, quantifying more than 1,500 proteins per motor neuron in brain and spinal cord tissue. A small pilot study revealed an increased immune response within motor neurons in tissue from people with C9 ALS compared to tissue from healthy controls. Taken together with Dr. Gate’s data, inflammation is occurring both within neurons and across immune cells in the brain.

Target ALS Springboard Fellow, Baylor College of Medicine

When neurons are under stress, they generate toxic lipid byproducts that normally get handed off to glial cells to clean up. In ALS and Frontotemporal Dementia (FTD), this cleanup system is disrupted. Dr. Goodman is studying whether the proteins Tau and TDP-43 in glial cells make lipid damage worse. The potential impact is twofold: first, her work could point to new lipid-based biomarkers, and second, it could reveal glial lipid droplets as a potential therapeutic target.

Target ALS Springboard Fellow, Icahn School of Medicine at Mount Sinai

People with ALS often experience blood-brain barrier leaks and inflammation in the cells lining blood vessels, signs that the immune system and vascular system are tightly linked in the disease process. A rare genetic variant in a gene called CREB3 appears to strengthen vascular health and lower ALS risk. Dr. Lopez-Lee is evaluating whether boosting CREB3 protein levels can restore healthy immune and vascular function. She’s also identifying additional vascular proteins that provide resilience. Her work could lead to development of new treatments that strengthen the brain’s vascular system and reduce damage.