ADDRESSING THE METABOLIC AND FUNCTIONAL DEFECTS IN NEURONS AND OLIGODENDROCYTES IN NASU HAKOLA DISEASE

Nasu-Hakola Disease (NHD) is a rare genetic disorder which manifests in young adulthood. People with NHD experience repeated bone fractures and later develop serious changes in behavior and memory. Over time, these changes become more severe leading to dementia and ultimately death, usually before the age of 50. The disease is caused by mutations in one of two specific genes, TREM2 and DAP12. These genes are active in brain cells called microglia, which help keep the brain healthy. Although we know these genes are involved, we still don’t understand how their malfunction leads to the NHD symptoms. Currently, there is no cure. Our group is expert in microglia, especially in TREM2-deficient mice, linked to NHD. We discovered that when TREM2 is missing, neurons begin to show signs of dysfunction early in life. They can’t produce energy properly, and the connections between them start to break down. This suggests that NHD may begin much earlier than we thought—possibly during brain development—long before symptoms appear. Our early findings also show that the absence of TREM2 also affects brain cells called oligodendrocytes, which are responsible for forming the protective coating (myelin) around nerve fibers. This means that both the communication between brain cells and the insulation of nerve fibers may be impaired from an early stage in people with NHD. By focusing our research on these early stages of brain development, we hope to uncover new ways to understand, diagnose, and eventually treat NHD before it causes irreversible damage.