Nicole Coufal, MD, Ph.D. (University of California, San Diego US)
In 2019, a $50,000 young investigator award was granted to Nicole Coufal with the University of California, San Diego. Study Title: “Pathophysiology of Neurodegenerative Erdheim-Chester Disease and Langerhans Cell Histiocytosis” The long-term goal of this project is to not only improve the understanding of ECD and LCH (Langerhans Cell Histiocytosis) associated neurodegeneration but to generate hypotheses and models that will allow for novel drug screening paradigms to improve the treatment of the devastating neurological form of this disease.
Amount: 50,000 USD
Final Report
Neurological symptoms and neurodegeneration occur in both Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) and vary from leukoencephalopathy to late progressive neurodegeneration but commonly include evidence of active demyelination. Microglia are the immune cells of the brain and are heavily implicated in neurodegenerative disease. In general, microglia in neurodegenerative disorders are often viewed as a secondary process, and it is unclear whether microglia activation is protective or harmful. One potential way in which the blood-borne mutation could lead to neurodegeneration in LCH and ECD is that the blood cells carrying the mutation become abnormal microglia and these activated BRAF mutated microglia cause brain damage and ultimately neurodegenerative symptoms. However, the data in human patients to date is limited and there are no human models for LCH or ECD at present – not for neurodegeneration or for LCH/ECD in general. Neurodegeneration in both LCH and ECD is variably responsive to treatment and often debilitating.
We have generated the first human model of LCH/ECD in a dish using patient-derived blood samples to generate patient-specific stem cells (induced pluripotent stem cells) to make microglia from the same patient cell line carrying one of the most common mutations seen in LCH/ECD patients, the BRAF(V600E) mutation. We have found that microglia with the BRAF(V600E) mutation are more activated and hyperinflammatory but also have a specific defect in their ability to phagocytose neurodegenerative relevant stimuli such as amyloid beta, whereas their normal phagocytosis is intact. This suggests that there are several ways in which BRAF(V600E) mutation carrying microglia may contribute to neurodegeneration – not only through inflammation but also through an inability to properly clear the brain of neurodegeneration-associated proteins such as amyloid plaques.