title: Evidence for autophagic gridlock in aging and neurodegeneration.
abstract: Autophagy is essential to neuronal homeostasis, and its impairment is implicated in the development of neurodegenerative pathology. However, the underlying mechanisms and consequences of this phenomenon remain a matter of conjecture. We show that misexpression of human tau in Drosophila induces accumulation of autophagic intermediates with a preponderance of large vacuoles, which we term giant autophagic bodies (GABs), which are reminiscent of dysfunctional autophagic entities. Lowering basal autophagy reduces GABs, whereas increasing autophagy decreases mature autolysosomes. Induction of autophagy is also associated with rescue of the tauopathy phenotype, suggesting that formation of GABs may be a compensatory mechanism rather than a trigger of neurodegeneration. Last, we show that the peculiar Biondi bodies observed in the choroid epithelium of both elderly and Alzheimer's disease human brains express immunoreactive markers similar to those of GABs. Collectively, these data indicate that autophagic gridlock contributes to the development of pathology in aging and neurodegeneration.
authors.affiliation: School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Tex; Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Tex.
authors.forename: Mathieu F
authors.initials: MF
authors.lastname: Bakhoum
authors.affiliation: School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Tex.
authors.forename: Christine Y
authors.initials: CY
authors.lastname: Bakhoum
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Tex.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Ding
authors.affiliation: School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Tex; Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Tex.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Carlton
authors.affiliation: School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Tex; Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, Tex.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Campbell
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Tex; Department of Neurology, The University of Texas Medical Branch at Galveston, Galveston, Tex; Department of Neurology, Baylor College of Medicine, and Parkinson's Disease Research Education and Clinical Center, Michael E. DeBakey VA Medical Center, Houston, Tex. Electronic address: george.jackson6@va.gov.
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005838:Genotype; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D012160:Retina / Q000166:cytology / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins; D020123:Sirolimus