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; Shao, Lin; Okeke, Ifechukwu; Camilli, Pietro De; Colón-Ramos, Daniel A.

doi:10.1101/2020.12.28.424508

Cited by 13 publications

(35 citation statements)

References 111 publications

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“…Local autophagosome formation at synapses is associated with the degradation of local synaptic cargo 6,15,27,[106][107][108][109][110][111] , and ATG-9 trafficking at presynaptic sites via exo-endocytosis could link synaptic activity states with local synaptic autophagy 12,21 . We find that the active zone protein CLA-1L regulates ATG-9 trafficking during its exo-endocytosis at presynaptic sites.…”

Section: Discussionmentioning

confidence: 99%

Section: Atg-9 Is Enriched At Endocytic Intermediates In Cla-1(l) Mutantsmentioning

confidence: 99%

“…ATG-9 undergoes exo-endocytosis at presynaptic sites, using synaptic vesicle cycling machinery 21 . The cla-1(L) phenotype is reminiscent of that seen for synaptic vesicle endocytosis mutants such as unc-26/synaptojanin 1, in which ATG-9 accumulates in purported endocytic intermediates, and abnormally colocalizes with the clathrin heavy chain subunit, CHC-1 (Figure S2A-E) 21 . To determine if, in cla-1(L) mutants, ATG-9 similarly abnormally accumulates in clathrin-rich endocytic intermediates, we examined the colocalization between ATG-9 and CHC-1 in wild type and cla-1(ola285) mutant animals.…”

Section: Atg-9 Is Enriched At Endocytic Intermediates In Cla-1(l) Mutantsmentioning

confidence: 99%

“…Previously we observed the average number of LGG-1 puncta increased in AIY when the wildtype animals were cultivated at 25°C 15 , a condition known to increase the activity state of the AIY neurons 95 . Worms with impaired exocytosis (in unc-13 mutants) or impaired autophagy (in atg-9 mutants) failed to display increased LGG-1 synaptic puncta 15,21 . We found that, unlike wild type animals, the average number of LGG-1 puncta did not increase in cla-1(L) mutants (alleles ola285 and ok560) in response to cultivation temperatures that increase the activity state of the neuron (Figure 8D and S5A).…”

Section: Disrupted Atg-9 Trafficking In Cla-1(l) Mutants Is Associated With a Deficit In Activity-induced Autophagosome Formationmentioning

confidence: 99%

“…Regulated steps in neurons include temporal and spatial control of autophagosome biogenesis near synaptic sites and in response to increased neuronal activity states [7][8][9][10][11][12][13][14][15][16][17][18] . The spatial regulation of autophagosome biogenesis at synapses results in part from directed transport of autophagic proteins to presynaptic sites and their local trafficking at the synapse 7,11,12,[19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy

Zhao

Yang

Hill

et al. 2021

Preprint

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In neurons, autophagy is temporally and spatially regulated to occur near presynaptic sites. How trafficking of autophagy proteins is regulated to support synaptic autophagy is not well understood. From forward genetic screens, we identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating trafficking of autophagy protein ATG-9 at synapses, and presynaptic autophagy. ATG-9 is a transmembrane protein that undergoes activity-dependent exo-endocytosis at synapses, and mutations in CLA-1L result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates. CLA-1L extends from the active zone to the periactive zone, and genetically interacts with periactive zone proteins required for clathrin-dependent endocytosis. We find that CLA-1L is specifically required for sorting of ATG-9 at synapses, likely via endosome-mediated endocytosis, and for activity-dependent presynaptic autophagy. Our findings provide mechanistic insights into how active zone proteins regulate key steps of ATG-9 exo-endocytosis, a process that could couple the activity state of the neuron and autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Atg-9 Is Enriched At Endocytic Intermediates In Cla-1(l) Mutantsmentioning

confidence: 99%

Section: Atg-9 Is Enriched At Endocytic Intermediates In Cla-1(l) Mutantsmentioning

confidence: 99%

Section: Disrupted Atg-9 Trafficking In Cla-1(l) Mutants Is Associated With a Deficit In Activity-induced Autophagosome Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy

Zhao

Yang

Hill

et al. 2021

Preprint

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Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease

Vidyadhara

Somayaji

Wade

et al. 2022

Preprint

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Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin-knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. We demonstrate that auxilin KO mice display the cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Through unbiased proteomic and neurochemical analyses, we demonstrate that dopamine homeostasis is disrupted in auxilin KO brains, including via slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. We also show that elevated macroautophagy and defective SV protein sorting contribute to ineffective dopamine sequestration and homeostasis, ultimately leading to neurodegeneration. This study advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.

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NDR1/2 kinases regulate membrane trafficking, enable efficient autophagy and prevent neurodegeneration

Ultanir

Rosianu

Mihaylov

et al. 2022

Preprint

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NDR1 and NDR2 are highly conserved kinases that regulate neuronal development, mitochondrial health and autophagy, but their roles in the mammalian brain in vivo are unexplored. Using constitutive Ndr1 and neuron-specific Ndr2 knockout mice we show that dual loss of Ndr1/2 in neurons causes neurodegeneration. Phosphoproteomic comparisons between Ndr1/2 knockout and control brains revealed novel kinase substrates and highlighted changes in endocytosis in the absence of NDR1/2. The endocytic protein Raph1/Lpd1 is a new NDR1/2 substrate and both NDR1/2 and Raph1 are critical for endocytosis and membrane recycling. NDR1/2 knockout brains exhibited a prominent accumulation of transferrin receptor, p62 and ubiquitinated proteins, indicative of a major impairment in protein homeostasis. Furthermore, autophagosome levels were reduced in knockout neurons, implying that reduced autophagy efficiency mediates p62 accumulation. Mechanistically, pronounced mislocalisation of the transmembrane autophagy protein ATG9A at the neuronal periphery, impaired axonal ATG9A trafficking and increased ATG9A surface levels further confirm defects in membrane trafficking and could underlie the impairment in autophagy. We provide novel insight into the roles of NDR1/2 kinases in maintaining neuronal health.

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

Cited by 13 publications

References 111 publications

The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy

The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy

Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease

NDR1/2 kinases regulate membrane trafficking, enable efficient autophagy and prevent neurodegeneration

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