A MITOCHONDRIAL CONNECTION BETWEEN FAULTY DEVELOPMENT AND NEURODEGENERATION OF CEREBELLUM AND SPINAL CORD: THE ROLE OF AFG3L2 IN MITOCHONDRIAL DYNAMICS AND METABOLISM

Mitochondrial protease AFG3L2 assembles with its homologous protein, paraplegin, to form the m-AAA complex in charge of essential protein quality control within mitochondria. Mutations of paraplegin cause Hereditary Spastic Paraplegia, a neurodegenerative disorder characterized specifically by axonal degeneration of the upper motoneurons. We obtained two Afg3l2 mutant mice carrying different genetic alterations but both resulting in depletion of Afg3l2 activity. In contrast with the late onset axon degeneration observed in paraplegin null model, Afg3l2 mutants show a severe neurological phenotype associated to muscular weakness, rigidity and atrophy. The syndrome progresses rapidly and homozygotes do not survive beyond 15-16 days. We detect defects in cerebellar and axonal development characterized by delayed myelination and impairment of axonal radial growth. Moreover, mitochondrial morphology abnormalities are evident in neurons, where the enzymatic activities of the respiratory chain complexes I and III are strikingly reduced. Mutant heterozygous Afg3l2 mice are also compromised. These mice show a significant motor impairment by 4 months of age. We identified also alterations in cerebellum architecture that correlates well with the observed motor dysfunction. The present project proposes to dissect the molecular events that link the dysfunction of m-AAA complexes to spinal cord and cerebellum development in the homozygous mice and to cerebellar neurodegeneration in the heterozygote. Preliminary evidences address our investigation towards axonal-glia interplay, intrinsic apoptosis pathway and mitochondrial molecular dynamics.