Dissection of molecular and functional processes in Nasu–Hakola disease, a primary microglial disorder of the CNS

Nasu-Hakola disease, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, is a rare genetic disease characterized by brain symptoms associated with recurrent bone fractures due to osseous lesions. The disease starts manifesting during young adulthood. During the third or fourth decade of life, patients present with pronounced personality changes (e.g. euphoria, lack of concentration, loss of judgment and social inhibitions) and display initially mild, but progressive, memory disturbances. Subsequently, patients progress to a profound dementia, become unable to speak and move, and usually die by the age of 50 years. Although it is established that the disease is caused by mutations in either of two genes -TREM2 or DAP12-  expressed by a population of brain cells known as microglia, the mechanisms involved are still unknown and no therapy is available. My research group has several years experience in the study of microglia, specifically in mice deficient of the gene causative of Nasu-Hakola disease, TREM2. Results of our studies on TREM2 have obtained high recognition by the scientific community. We believe therefore to be in the best condition to attempt the identification of the molecular mechanisms involved in the Nasu-Hakola disease and to trace their appearance during development. We will use a combination of advanced methodologies which are currently in place in our laboratory and we will take advantage of a solid set of preliminary results. Our final goal is to unveil key molecular targets for the disease, in order to accelerate the development of a therapy.