title: Neuronal glycogen synthesis contributes to physiological aging.
abstract: Glycogen is a branched polymer of glucose and the carbohydrate energy store for animal cells. In the brain, it is essentially found in glial cells, although it is also present in minute amounts in neurons. In humans, loss-of-function mutations in laforin and malin, proteins involved in suppressing glycogen synthesis, induce the presence of high numbers of insoluble polyglucosan bodies in neuronal cells. Known as Lafora bodies (LBs), these deposits result in the aggressive neurodegeneration seen in Lafora's disease. Polysaccharide-based aggregates, called corpora amylacea (CA), are also present in the neurons of aged human brains. Despite the similarity of CA to LBs, the mechanisms and functional consequences of CA formation are yet unknown. Here, we show that wild-type laboratory mice also accumulate glycogen-based aggregates in the brain as they age. These structures are immunopositive for an array of metabolic and stress-response proteins, some of which were previously shown to aggregate in correlation with age in the human brain and are also present in LBs. Remarkably, these structures and their associated protein aggregates are not present in the aged mouse brain upon genetic ablation of glycogen synthase. Similar genetic intervention in Drosophila prevents the accumulation of glycogen clusters in the neuronal processes of aged flies. Most interestingly, targeted reduction of Drosophila glycogen synthase in neurons improves neurological function with age and extends lifespan. These results demonstrate that neuronal glycogen accumulation contributes to physiological aging and may therefore constitute a key factor regulating age-related neurological decline in humans.
authors: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors: Christopher
authors: C
authors: Sinadinos
authors: Jordi
authors: J
authors: Valles-Ortega
authors: Laura
authors: L
authors: Boulan
authors: Estel
authors: E
authors: Solsona
authors: Maria F
authors: MF
authors: Tevy
authors: Mercedes
authors: M
authors: Marquez
authors: Jordi
authors: J
authors: Duran
authors: Carmen
authors: C
authors: Lopez-Iglesias
authors: Joaquim
authors: J
authors: Calbó
authors: Ester
authors: E
authors: Blasco
authors: Marti
authors: M
authors: Pumarola
authors: Marco
authors: M
authors: Milán
authors: Joan J
authors: JJ
authors: Guinovart
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004331:Drosophila melanogaster; D005260:Female; D005936:Glucans / Q000096:biosynthesis; D006003:Glycogen / Q000096:biosynthesis*; D006006:Glycogen Synthase / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*
chemical_list: D005936:Glucans; D006360:Heat-Shock Proteins; D006003:Glycogen; C083094:polyglucosan; D006006:Glycogen Synthase
keywords: Drosophila; aging; corpora amylacea; glycogen; protein aggregation; stress response