Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.

SUMMARY Autophagy is a cellular degradation process essential for neuronal development and survival. Neurons are highly polarized cells in which autophagosome biogenesis is spatially compartmentalized. The mechanisms and physiological importance of this spatial compartmentalization of autophagy in the neuronal development of living animals are not well understood. Here we determine that, in C. elegans neurons, autophagosomes form near synapses and are required for neurodevelopment. We first determine, through unbiased genetic screens and systematic genetic analyses, that autophagy is required cell-autonomously for presynaptic assembly and for axon outgrowth dynamics in specific neurons. We observe autophagosome biogenesis in the axon near synapses, and this localization depends on the synaptic vesicle kinesin, KIF1A/UNC-104. KIF1A/UNC-104 coordinates localized autophagosome formation by regulating the transport of the integral membrane autophagy protein, ATG-9. Our findings indicate that autophagy is spatially regulated in neurons through the transport of ATG-9 by KIF1A/UNC-104 to regulate neurodevelopment.

Autophagy is a cellular degradation process essential for neuronal development and survival.Neurons are highly polarized cells in which autophagosome biogenesis is spatially compartmentalized. The mechanisms and physiological importance of this spatial compartmentalization of autophagy in the neuronal development of living animals are not well understood. Here we determine that, in C. elegans neurons, autophagosomes form near synapses and are required for neurodevelopment. We first determined, through unbiased genetic screens and systematic genetic analyses, that autophagy is required cell-autonomously for presynaptic assembly and for axon outgrowth dynamics in specific neurons. We observe autophagosomes in the axon near synapses, and this localization depends on the synaptic vesicle kinesin, KIF1A/UNC-104. KIF1A/UNC-104 coordinates localized autophagosome formation by regulating the transport of the integral membrane autophagy protein, ATG-9. Our findings indicate that autophagy is spatially regulated in neurons through the transport of ATG-9 by KIF1A/UNC-104 to regulate neurodevelopment. 3 HIGHLIGHTS and eTOC Blurb• The autophagy pathway is required for synaptic assembly in vivo • The autophagy pathway acts cell-autonomously and in specific neurons in development• Autophagosome biogenesis occurs in compartmentalized axonal regions near synapses • The synaptic vesicle kinesin UNC-104/KIF1A transports ATG-9 to presynaptic sites . Consistent with wy56 being an allele of atg-9, we also observed that wy56 fails to complement atg-9(bp564) and that expression of the ATG-9 cDNA under an early panneuronal promoter (punc-14) rescues the atg-9 presynaptic phenotype in AIY ( Figure 1G).Together, our genetic data indicate that wy56 is a nonsense, loss-of-function mutation in the atg-9 gene. The autophagy pathway is required for clustering of synaptic vesicle proteins in AIYThe atg-9 gene encodes a conserved, six-pass transmembrane protein that acts in the autophagy pathway (Lang et al., 2000; Noda et al., 2000; Young et al., 2006). Since ATG-9 is primarily known for regulating autophagosome biogenesis, we examined whether other components of the autophagy pathway are also required for synaptic vesicle clustering during synaptogenesis. Autophagosome biogenesis can be divided into four steps: initiation, nucleation, elongation, and retrieval. Distinct and specialized protein complexes mediate these steps, and orthologs for these protein complexes have been identified in C. elegans (Figures 2A, S3G and Table S1) (Melendez and Levine, 2009; Tian et al., 2010). To evaluate the requirement of each of these distinct steps in synaptic vesicle clustering, we systematically examined existing alleles for each of these orthologs using synaptic vesicle markers GFP::RAB-3 and SNB-1::YFP (Figures 2, S1 and S3).Autophagy is induced by a kinase complex composed of UNC-51/Atg1/ULK, EPG-9/Atg101 and ATG-13/EPG-1 (Feng et al., 2014; Kamada et al., 2000; Melendez and Levine, 2009; Reggiori et al., 2004). Examination of putative null allel...

A signaling module known to organize the actin cytoskeleton during neuronal guidance also instructs synaptic vesicle clustering during synapse assembly.

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