Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

Yang, Sisi; Park, Daehun; Manning, Laura; Hill, Sarah E.; Cao, Mian; Zhao, Xuan; Gonzalez, Ian; Dong, Yongming; Clark, Benjamin A.; Shao, Lin; Okeke, Ifechukwu; Almoril-Porras, Agustin; Bai, Jihong; Camilli, Pietro De; Colón-Ramos, Daniel A.

doi:10.1016/j.neuron.2021.12.031

Cited by 61 publications

(71 citation statements)

References 144 publications

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“…The mechanisms that couple autophagosome biogenesis locally at synapses to neuronal activity are still unknown but it has been suggested that trafficking of ATG9, which is the only TM protein in the core autophagy pathway, links the SV cycle to autophagy in C. elegans (Fig 5) (Yang et al, 2022). Interestingly, ATG9 is generated from the TGN and undergoes exo-endocytosis at presynaptic sites in an activity-dependent manner (Yang et al, 2022). Thus, ATG9 exo-endocytosis and subsequent endocytosis might be instrumental in autophagosome biogenesis at presynaptic sites based on an intimate link with the activity-dependent synaptic vesicle cycle (Yang et al, 2022).…”

Section: The Formation Of Autophagosomes Is Enhanced By Synaptic Acti...mentioning

confidence: 99%

“…Autophagy is enhanced at boutons upon increased synaptic activity (Wang et al, 2015;Soukup et al, 2016) and one might speculate that activity-dependent autophagy has functions that could differ from basal autophagy (Andres-Alonso et al, 2021; . The mechanisms that couple autophagosome biogenesis locally at synapses to neuronal activity are still unknown but it has been suggested that trafficking of ATG9, which is the only TM protein in the core autophagy pathway, links the SV cycle to autophagy in C. elegans (Fig 5) (Yang et al, 2022). Interestingly, ATG9 is generated from the TGN and undergoes exo-endocytosis at presynaptic sites in an activity-dependent manner (Yang et al, 2022).…”

Section: The Formation Of Autophagosomes Is Enhanced By Synaptic Acti...mentioning

confidence: 99%

“…Interestingly, ATG9 is generated from the TGN and undergoes exo-endocytosis at presynaptic sites in an activity-dependent manner (Yang et al, 2022). Thus, ATG9 exo-endocytosis and subsequent endocytosis might be instrumental in autophagosome biogenesis at presynaptic sites based on an intimate link with the activity-dependent synaptic vesicle cycle (Yang et al, 2022). The presence of GS has been reported in axons (Cornejo et al, 2020), and this raises the intriguing possibility that ATG might traffic from local axonal Golgi membranes to boutons (Fig 5).…”

Section: The Formation Of Autophagosomes Is Enhanced By Synaptic Acti...mentioning

confidence: 99%

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The needs of a synapse—How local organelles serve synaptic proteostasis

et al. 2022

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Synaptic function crucially relies on the constant supply and removal of neuronal membranes. The morphological complexity of neurons poses a significant challenge for neuronal protein transport since the machineries for protein synthesis and degradation are mainly localized in the cell soma. In response to this unique challenge, local micro‐secretory systems have evolved that are adapted to the requirements of neuronal membrane protein proteostasis. However, our knowledge of how neuronal proteins are synthesized, trafficked to membranes, and eventually replaced and degraded remains scarce. Here, we review recent insights into membrane trafficking at synaptic sites and into the contribution of local organelles and micro‐secretory pathways to synaptic function. We describe the role of endoplasmic reticulum specializations in neurons, Golgi‐related organelles, and protein complexes like retromer in the synthesis and trafficking of synaptic transmembrane proteins. We discuss the contribution of autophagy and of proteasome‐mediated and endo‐lysosomal degradation to presynaptic proteostasis and synaptic function, as well as nondegradative roles of autophagosomes and lysosomes in signaling and synapse remodeling. We conclude that the complexity of neuronal cyto‐architecture necessitates long‐distance protein transport that combines degradation with signaling functions.

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Section: The Formation Of Autophagosomes Is Enhanced By Synaptic Acti...mentioning

confidence: 99%

Section: The Formation Of Autophagosomes Is Enhanced By Synaptic Acti...mentioning

confidence: 99%

Section: The Formation Of Autophagosomes Is Enhanced By Synaptic Acti...mentioning

confidence: 99%

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The needs of a synapse—How local organelles serve synaptic proteostasis

et al. 2022

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“…For example, Endophilin-A and Synaptojanin, proteins important for synaptic vesicle endocytosis, can regulate autophagy ( George et al, 2016 ; Soukup et al, 2016 ; Vanhauwaert et al, 2017 ), while the presynaptic scaffolding protein Bassoon inhibits autophagic biogenesis ( Okerlund et al, 2017 ). Synaptic activity regulates autophagy via modification of the presynaptic location of the core autophagy protein Atg9 ( Yang et al, 2022 ). On the other hand, autophagy regulates synaptic activity, as impaired autophagy causes axonal ER accumulation and increased neurotransmission ( Kuijpers et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The role of autophagic kinases in regulation of axonal function

Berth

Rich

Lloyd

2022

Front. Cell. Neurosci.

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Autophagy is an essential process for maintaining cellular homeostasis. Highlighting the importance of proper functioning of autophagy in neurons, disruption of autophagy is a common finding in neurodegenerative diseases. In recent years, evidence has emerged for the role of autophagy in regulating critical axonal functions. In this review, we discuss kinase regulation of autophagy in neurons, and provide an overview of how autophagic kinases regulate axonal processes, including axonal transport and axonal degeneration and regeneration. We also examine mechanisms for disruption of this process leading to neurodegeneration, focusing on the role of TBK1 in pathogenesis of Amyotrophic Lateral Sclerosis.

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“…To determine whether ATG-9 locates on vesicles at synapses, we performed post-embedding immunogold electron microscopy on transgenic C. elegans animals expressing ATG-9::GFP in neurons [ 1 ]. We observe that ATG-9 localizes on a subpopulation of vesicles at synapses.…”

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confidence: 99%

Transmembrane protein ATG-9 links presynaptic autophagy with the synaptic vesicle cycle

Yang

Colón-Ramos

2022

Autophagy

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Macroautophagy/autophagy occurs preferentially at synapses and responds to increased neuronal activity states. How synaptic autophagy is coupled to the neuronal activity state is largely unknown. Through genetic approaches we find that ATG-9, the only transmembrane protein in the core autophagy pathway, is transported from the trans -Golgi network to synapses in C. elegans via the AP-3 complex. At synapses ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt the endocytosis pathway, including a mutation associated with early onset Parkinsonism (EOP), lead to abnormal ATG-9 accumulation into subsynaptic clathrin-rich foci, and defects in activity-induced synaptic autophagy. We propose that ATG-9 exo-endocytosis links the activity-dependent synaptic vesicle cycle with autophagosome formation at synapses.

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Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

Cited by 61 publications

References 144 publications

The needs of a synapse—How local organelles serve synaptic proteostasis

The needs of a synapse—How local organelles serve synaptic proteostasis

The role of autophagic kinases in regulation of axonal function

Transmembrane protein ATG-9 links presynaptic autophagy with the synaptic vesicle cycle

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