title: A forward genetic screen in Drosophila implicates insulin signaling in age-related locomotor impairment.
abstract: Age-related locomotor impairment (ARLI) is one of the most detrimental changes that occurs during aging. Elderly individuals with ARLI are at increased risks for falls, depression and a number of other co-morbidities. Despite its clinical significance, little is known about the genes that influence ARLI. We consequently performed a forward genetic screen to identify Drosophila strains with delayed ARLI using negative geotaxis as an index of locomotor function. One of the delayed ARLI strains recovered from the screen had a P-element insertion that decreased expression of the insulin signaling gene phosphoinositide-dependent kinase 1 (PDK1) Precise excision of the P-element insertion reverted PDK1 expression and ARLI to the same as control flies, indicating that disruption of PDK1 leads to delayed ARLI. Follow-up studies showed that additional loss of function mutations in PDK1 as well as loss of function alleles of two other insulin signaling genes, Dp110 and Akt (the genes for the catalytic subunit of phosphoinositide 3-kinase and AKT), also forestalled ARLI. Interestingly, only some of the strains with delayed ARLI had elevated resistance to paraquat, indicating that enhanced resistance to this oxidative stressor is not required for preservation of locomotor function across age. Our studies implicate insulin signaling as a key regulator of ARLI in Drosophila.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Jones
authors.forename: Julia Warner
authors.initials: JW
authors.lastname: Gargano
authors.forename: Devin
authors.initials: D
authors.lastname: Rhodenizer
authors.forename: Ian
authors.initials: I
authors.lastname: Martin
authors.forename: Poonam
authors.initials: P
authors.lastname: Bhandari
authors.forename: Mike
authors.initials: M
authors.lastname: Grotewiel
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; C119015:LOCO protein, Drosophila; D009419:Nerve Tissue Proteins; D058539:Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin