title: Delayed glial clearance of degenerating axons in aged Drosophila is due to reduced PI3K/Draper activity.
abstract: Advanced age is the greatest risk factor for neurodegenerative disorders, but the mechanisms that render the senescent brain vulnerable to disease are unclear. Glial immune responses provide neuroprotection in a variety of contexts. Thus, we explored how glial responses to neurodegeneration are altered with age. Here we show that glia-axon phagocytic interactions change dramatically in the aged Drosophila brain. Aged glia clear degenerating axons slowly due to low phosphoinositide-3-kinase (PI3K) signalling and, subsequently, reduced expression of the conserved phagocytic receptor Draper/MEGF10. Importantly, boosting PI3K/Draper activity in aged glia significantly reverses slow phagocytic responses. Moreover, several hours post axotomy, early hallmarks of Wallerian degeneration (WD) are delayed in aged flies. We propose that slow clearance of degenerating axons is mechanistically twofold, resulting from deferred initiation of axonal WD and reduced PI3K/Draper-dependent glial phagocytic function. Interventions that boost glial engulfment activity, however, can substantially reverse delayed clearance of damaged neuronal debris.
authors.affiliation: Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Purice
authors.affiliation: Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Speese
authors.affiliation: Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Logan
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D019771:Axotomy; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000502:physiology*; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D050791:STAT Transcription Factors; D058570:TOR Serine-Threonine Kinases; C105675:Stat92E protein, Drosophila; C495322:drpr protein, Drosophila; C416303:target of rapamycin protein, Drosophila