title: Delayed Induction of Human NTE (PNPLA6) Rescues Neurodegeneration and Mobility Defects of Drosophila swiss cheese (sws) Mutants.
abstract: Human PNPLA6 gene encodes Neuropathy Target Esterase protein (NTE). PNPLA6 gene mutations cause hereditary spastic paraplegia (SPG39 HSP), Gordon-Holmes syndrome, Boucher-Neuhäuser syndromes, Laurence-Moon syndrome, and Oliver-McFarlane syndrome. Mutations in the Drosophila NTE homolog swiss cheese (sws) cause early-onset, progressive behavioral defects and neurodegeneration characterized by vacuole formation. We investigated sws5 flies and show for the first time that this allele causes progressive vacuolar formation in the brain and progressive deterioration of negative geotaxis speed and endurance. We demonstrate that inducible, neuron-specific expression of full-length human wildtype NTE reduces vacuole formation and substantially rescues mobility. Indeed, neuron-specific expression of wildtype human NTE is capable of rescuing mobility defects after 10 days of adult life at 29°C, when significant degeneration has already occurred, and significantly extends longevity of mutants at 25°C. These results raise the exciting possibility that late induction of NTE function may reduce or ameliorate neurodegeneration in humans even after symptoms begin. In addition, these results highlight the utility of negative geotaxis endurance as a new assay for longitudinal tracking of degenerative phenotypes in Drosophila.
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Alyson
authors.initials: A
authors.lastname: Sujkowski
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Shirley
authors.initials: S
authors.lastname: Rainier
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Geriatric Research Education and Clinical Center, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: John K
authors.initials: JK
authors.lastname: Fink
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wessells
mesh_terms: D000375:Aging; D000818:Animals; D018450:Disease Progression; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000502:physiology*; D006801:Humans; D008136:Longevity; D009043:Motor Activity; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010740:Phospholipases / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D010740:Phospholipases; C108350:SWS protein, Drosophila; C586915:PNPLA6 protein, human; D000217:Acyltransferases