Functional characterization of Drosophila models of SEPTIN11-associated neurodegeneration.

Hereditary ataxias are severe neurodegenerative disorders characterized by progressive loss of coordination in voluntary muscle movement. Due to clinical and genetic heterogeneity, the overall genetic diagnosis rate is between 55-65% suggesting there might be disease-causing genes yet to be identified. Previously, while screening a cohort with early-onset severe neurodegeneration, I identified the SEPTIN11 gene as a novel disease-causing candidate in a family presenting with hereditary ataxia and axonal sensorimotor polyneuropathy. The studies in the literature are suggestive that dysregulation of members of the septin protein family could lead to neurodegeneration, however, this is not sufficient to prove SEPTIN11 pathogenicity in the nervous system. Since the family we reported is the sole family in the literature, the only approach to provide concrete evidence of pathogenicity is to generate an animal model for assessing neurodegeneration in a physiologically relevant context. Building on the genetic evidence and promising preliminary data based on septin knock-out flies and humanized transgenic flies expressing wild-type and mutant human SEPTIN11, I would like to further characterize hallmarks of neurodegeneration potentially led by SEPTIN11 dysregulation. This in-depth analysis will provide indisputable evidence of pathogenicity likely associated with the (mal)functioning of SEPTIN11 in the central and peripheral nervous systems.

Keywords:MOLECULAR NEUROPATHOLOGY, PERIPHERAL NEUROPATHY, DROSOPHILA MELANOGASTER, HEREDITARY ATAXIA

Disciplines:Genetically modified animals, Genetics, Neurological and neuromuscular diseases