MOLECULAR CHARACTERIZATION OF SEN1/SETX-CONTROLLED PATHWAYS DEFECTIVE IN THE AOA2 AND ASL4 NEURODEGENERATIVE SYNDROMES

The rare neurodegenerative diseases AOA2 and ASL4 are both caused by mutations in the senataxin gene. AOA2 is an autosomal recessive Ataxia disorder in which the progressive degeneration of the cerebellum results in loss of muscle coordination. ALS4 is an autosomal dominant form of juvenile amyotrophic lateral sclerosis in which the hallmark is degeneration of motor neurons in the brain and spinal cord that impedes muscle movements. The nature of SETX-associated mutations described in AOA2 and ASL4 patients suggests that the two diseases originate by diverse mechanisms of deregulation of SETX activities that, however, wait to be elucidated. As budding yeast also has senataxin, we intend to study the protein’s role normally and in neurodegenerative syndromes by introducing the disease-associated mutations in yeast senataxin SEN1 to see which cell processes might change. We also aim to use budding yeast to identify biological compounds that might restore the activity of mutated SETX proteins. Since budding yeast is a powerful model system for genetic and genomic studies, our study is expected to rapidly expand the knowledge of the molecular defects underlining AOA2 and ASL4 neurological syndromes and, at the same time, to help the identification of biological compounds for their clinical treatment.