HEREDITARY SPASTIC PARAPLEGIA DUE TO MITOCHONDRIAL DEFECTS. DEVELOPMENT OF ANIMAL AND CELLULAR MODELS OF PATHOGENESIS

Neurodegeneration is a feature common to all forms of hereditary spastic paraplegia (HSP. Mutations in paraplegin, a mitochondrial cause an autosomal recessive form of HSP. We have analyzed the function of paraplegin at the cellular level in HSP patient cells lacking this protein. We demonstrated that paraplegin assembles with the homologous AFG3L2 protein in the mitochondrial inner membrane forming a high molecular weight complex, which is missing in HSP patients’ cells. Loss of this complex in HSP patient cells cause mitochondrial defects. Here, we propose the investigation of the molecular mechanisms leading to HSP. This is accomplished by studying two systems, murine models and human cell lines, which both provide unique and complementary features.