DISSECTING THE ROLE OF TWO SPASTIN ISOFORMS WITH DIFFERENT SUBCELLULAR LOCALIZATION IN HEREDITARY SPASTIC PARAPLEGIA

Hereditary spastic paraplegia (HSP) is a progressive disease characterized by difficulty in walking, due to weakness and rigidity of the legs. The disease is of genetic origin and at present no cure is available to stop its progression. At the basis of the symptoms is the death of the long processes, called axons, of the neurons in our brain that are responsible for motor voluntary movements. When this happens, the brain looses its ability to control movements. In most case, HSP is due to mutations in the gene SPG4, which produces the protein spastin. The normal function of spastin is unknown. We have discovered that spastin comes in two different isoforms: a longer protein that is in the cytoplasm of the cells, and a shorter one that instead stays mainly in the nucleus. These isoforms have also different abilities to make interaction with other proteins. We now want to study the function of each spastin isoform separately, to understand their role in different cellular subcompartments and in the development of the disease. These studies are an important step to understand the sequence of events that lead to the death of axons of the motor neurons and therefore to HSP, and are preliminary to conceive successful therapeutical strategies for the patients.