Glial engulfment of dead neurons and neurites after trauma, during development and in neurodegenerative diseases plays a crucial role in nervous system maintenance. Axon debris generated after traumatic injury is cleared by phagocytic glia via Draper receptor signalling in Drosophila. However, mechanisms governing the efficiency of axon debris phagocytosis and degradation have remained largely unexplored. Here we show that glial LC3-associated phagocytosis (LAP), an engulfment pathway assisted by certain components of the macroautophagy machinery, promotes clearance of degenerating axons in the Drosophila wing nerve. A LAP-specific subset of autophagy-related (Atg) genes is required in glia for efficient debris elimination, which includes members of the Atg8a (LC3) conjugation system and the Vps34 lipid kinase complex subunits UVRAG and Rubicon but not Atg14 or the Atg1 kinase complex. Atg8a and Rubicon are recruited to Rab7-positive phagosomes and Atg8a lipid conjugation is essential for debris-containing phagosome maturation. Finally, Rubicon overexpression in glia accelerates axon debris elimination. Our results reveal the critical role of LAP in glia in the clearance of neuronal debris in vivo, with important implications for the recovery of the injured nervous system.

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A subset of patients with retinitis pigmentosa (RP) carry mutations in several spliceosomal components including the PRPF8 protein. Here, we established two alleles of murinePrpf8that genocopy or mimic aberrant PRPF8 found in RP patients—the substitution p.Tyr2334Asn and an extended protein variant p.Glu2331ValfsX15. Homozygous mice expressing the aberrant Prpf8 variants developed within the first 2 mo progressive atrophy of the cerebellum because of extensive granule cell loss, whereas other cerebellar cells remained unaffected. We further show that a subset of circRNAs were deregulated in the cerebellum of both Prpf8-RP mouse strains. To identify potential risk factors that sensitize the cerebellum for Prpf8 mutations, we monitored the expression of several splicing proteins during the first 8 wk. We observed down-regulation of all selected splicing proteins in the WT cerebellum, which coincided with neurodegeneration onset. The decrease in splicing protein expression was further pronounced in mouse strains expressing mutated Prpf8. Collectively, we propose a model where physiological reduction in spliceosomal components during postnatal tissue maturation sensitizes cells to the expression of aberrant Prpf8 and the subsequent deregulation of circRNAs triggers neuronal death.