Introduction: Autophagy is a cellular mechanism involved in the clearance of aggregated cytosolic proteins, and has been studied in relation to neurodegenerative disorders such as Parkinson’s disease and depression. This project aims to create a mouse model of neurodegenerative disease and affective disorder through a conditional, targeted knockout of the autophagy associated Atg 5 gene. Methods: Mice carrying a floxed Atg 5 allele were cross-bred with transgenic mice carrying a Cre-recombinase enzyme driven off an inducible, neuronally expressed promoter. Resultant progeny were genetically selected to carry both the floxed Atg 5 allele and the Cre recombinase, thus allowing induction of gene deletion to occur at a defined age. Conditional knockout mice were induced at 6 weeks of age and assessed via a battery of behavioral and physical tests, including open field, beam traversal, grip strength, RotaRod performance test, gait analysis, clasping analysis, black and white box, cookie preference, sweet solution preference test, amphetamine induced open field, and replenishment of L-Dopa. Results: Preliminary data suggests that deletion of the Atg 5 gene results in the development of a manic phenotype revealed by increased activity observed in the open field test within 5 weeks of gene deletion. No evidence of motor impairments was noted at this time point post induction. However, at 9 months post-induction a significant neurological phenotype emerged with knockout animals continuing to demonstrate increased open field activity, but now also demonstrating reduced ability to remain on the spinning RotaRod, reduced grip strength, abnormal gait, uncontrolled tremor, and abnormal clasping reflex. Discussion: Deletion of the Atg 5 gene results in age-dependent development of behavioral and physical changes associated with the phenotype of “mania” and “neurodegeneration”. This novel mouse model is amenable to screening studies for the discovery of novel small molecule drugs for the treatment of psychiatric and neurological disease.
University Honors Capstone Project Paper and Poster, University of Minnesota Duluth, 2018. Malia Triebold authored paper and poster; C.E. Anderson, H. Einat, and G.W. Anderson authored poster.
Triebold, Malia; Einat, H; Anderson, C.E; Anderson, G.W.
Using Conditional Autophagy Inhibition in Mice to Study Neurological Disorders.
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