L1-CAM-DISEASE (CRASH SYNDROME): EXPRESSION AND SYNAPTIC ROLE OF EXPRESSION AND SYNAPTIC ROLE OF L1-CAM AND ITS MUTATIONS; PHARMACOLOGY OF ITS SIGNALLING

The L1-CAM disease, also known as CRASH syndrome, is a hereditary form of dementia associated to the X chromosome that affects males. The disease, which includes other symptoms such as spastic paraplegia and hydrocephalus, is due to mutations of a protein exposed at the surface of neurons, called L1-CAM, which keeps neurons adherent to each other. In addition, upon activation by binding to itself or a different protein, L1-CAM triggers signals inside the cell, important to keep it in a differentiated state. The severity of the disease varies depending on the L1-CAM mutations. Some children die in the first year of life, others live almost normally. Numerous studies have been carried out about the L1-CAM disease, however various aspects remain unclear. We intend to investigate three such aspects that are important for the development of the disease; a) the mechanisms that control the expression of L1-CAM and their alterations occurring when the protein is mutated. These mechanisms have a role in the disease as a whole; b) the functioning of synapses, the connections between neurons, focusing on the processes that occur in the transmitting cells rather than in the cells that receive the transmission. These processes are important for thinking, therefore their lesion could have a role in dementia; c) the intracellular signals activated by L1-CAM, focusing on their control. This to start the investigation of drugs that could alleviate the symptoms of the disease. The studies will be carried out by an ample spectrum of investigation techniques, applied to various types of cells, from clones selected from a cell line to neurons differentiated from stem cells, neuronal cultures and brain slices of mice up to mice lacking L1-CAM, to be used as models of the disease. At the moment we have already the experimental tools (proteins, antibodies, cDNA etc.) as well as the know-how and experience to carry out the work.