THE NASU-HAKOLA DISEASE (PLOSL): CELLULAR MECHANISMS OF NEURODEGENERATION

Nasu-Hakola disease, otherwise indicated as polycistic membraneous osteodisplasia with sclerosing leukoenceephalopaythy, PLOSL, is distributed in all areas of the world. Unique among genetic diseases it affects two organs considered quite distinct from each other, i.e. bones and the brain. In the bones PLOSL induces the appearance of painful cysts, with ensuing fractures; in the brain numerous neurological symptoms (convulsions, primitive reflexes, brain atrophy) together with juvenile dementia appearing most often between 30 and 50 years of age. So far no therapy exists for this disease. Recent studies have revealed in PLOSL patients the existence of loss-of-function mutations in two types of cell surface proteins known to operate co-ordinately: the receptor TREM2 and its coupling protein, DAP12. These results have open the possibility to investigate the mechanisms by which lesions are established in the organ of PLOSL patients, a study necessary to develop rational therapeutic approaches to the disease. Our laboratory is specialized in the study of the nervous system. Our aim is therefore to investigate its lesions in PLOSL. Our preliminary experiments have shown that, in the normal human brain the TREM2/DAP12 system is expressed not by neurons, the typical nerve cells, but by microglia, another type of brain cell which is activated in many other brain diseases. Our study intends to clarify how comes that the TREM2/DAP12 defect, typical of PLOSL, affects the functioning of microglia and that of the other brain cells, astrocytes and neurons, leading to neurodegeneration. So far, these mechanisms are totally unknown. Knowledge of the mechanisms could provide hints for the identification of drugs able to protect neurons and thus to delay or prevent the appearance of neurological symptoms and the juvenile dementia in PLOSL patients.