Endosomal sorting protein SNX4 limits synaptic vesicle docking and release DOI Open Access

Josse Poppinga,

Nolan J. Barret,

L. Niels Cornelisse

et al.

Published: May 7, 2024

Sortin-Nexin 4 (SNX4) is an evolutionary conserved organizer of membrane recycling. In neurons, SNX4 accumulates in synapses, but how affects synapse function remains unknown. We generated a conditional knock-out mouse model and report that cKO synapses show enhanced neurotransmission during train stimulation, while the first evoked EPSC was normal. depletion did not affect vesicle recycling or levels localization SNARE-protein VAMP2/synaptobrevin-2. However, affected ultrastructure: increase docked synaptic vesicles at active zone, overall number normal, decreased zone length. These effects together lead to substantially increased density per release site. conclusion, negative regulator docking release. findings suggest role for recruitment zone.

Language: Английский

A GCC repeat in RAB26 undergoes natural selection in human and harbors divergent genotypes in late-onset Alzheimer’s disease DOI Open Access
Samira Alizadeh, Safoura Khamse,

Nahid Tajeddin

et al.

Gene, Journal Year: 2023, Volume and Issue: 893, P. 147968 - 147968

Published: Nov. 4, 2023

Language: Английский

Citations

8
PDZD8 promotes autophagy at ER-Lysosome contact sites to regulate synaptogenesis DOI Creative Commons
Rajan Thakur, Kate M. O’Connor-Giles

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 30, 2023

SUMMARY Building synaptic connections, which are often far from the soma, requires coordinating a host of cellular activities transcription to protein turnover, placing high demand on intracellular communication. Membrane contact sites (MCSs) formed between organelles have emerged as key signaling hubs for an array activities. We found that endoplasmic reticulum (ER) MCS tethering PDZD8 is required activity-dependent synaptogenesis. sufficient drive ectopic bouton formation through autophagy-dependent mechanism and basal synapse when autophagy biogenesis limited. functions at ER-late endosome/lysosome (LEL) MCSs promote lysosome maturation accelerate autophagic flux. Mutational analysis PDZD8’s SMP domain further suggests role lipid transfer ER-LEL MCSs. propose PDZD8-dependent ER LELs promotes increase flux during periods demand, including formation. GRAPHICAL ABSTRACT

Language: Английский

Citations

7
Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health DOI Open Access
Valerie Uytterhoeven, Patrik Verstreken, Eliana Nachman

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 224(2)

Published: Dec. 24, 2024

Synaptic dysfunction is one of the earliest cellular defects observed in Alzheimer's disease (AD) and Parkinson's (PD), occurring before widespread protein aggregation, neuronal loss, cognitive decline. While field has focused on aggregation Tau α-Synuclein (α-Syn), emerging evidence suggests that these proteins may drive presynaptic pathology even their aggregation. Therefore, understanding mechanisms by which α-Syn affect terminals offers an opportunity for developing innovative therapeutics aimed at preserving synapses potentially halting neurodegeneration. This review focuses molecular converge caused α-Syn. Both have physiological roles synapses. However, during disease, they acquire abnormal functions due to aberrant interactions mislocalization. We provide overview current research different essential pathways influenced Finally, we highlight promising therapeutic targets maintaining synaptic function both tauopathies synucleinopathies.

Language: Английский

Citations

2
Manganese-induced α-synuclein overexpression promotes the accumulation of dysfunctional synaptic vesicles and hippocampal synaptotoxicity by suppressing Rab26-dependent autophagy in presynaptic neurons DOI
Zhuo Ma, Kuan Liu, Ruifeng Zhang

et al.

The Science of The Total Environment, Journal Year: 2022, Volume and Issue: 858, P. 159753 - 159753

Published: Oct. 27, 2022

Language: Английский

Citations

7
Drosophila melanogaster Neuromuscular Junction as a Model to Study Synaptopathies and Neuronal Autophagy DOI
Anushka Chakravorty, Vasu Sheeba, Ravi Manjithaya

et al.

Methods in molecular biology, Journal Year: 2024, Volume and Issue: unknown, P. 97 - 120

Published: Jan. 1, 2024

Language: Английский

Citations

1
Neuronal autophagosomes are transported to astrocytes for degradation DOI
Katrin Linda, Imke M. E. Schuurmans, Hilde Smeenk

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 4, 2024

Abstract Autophagy is a vital catabolic process responsible for the degradation of cytosolic components, playing key role in cellular homeostasis and survival. At synapses, autophagy crucial regulating neuronal activity utilizes specialized machinery. While considerable progress has been made understanding initiation autophagosome formation, mechanisms governing clearance autophagosomes from synaptic sites remain poorly understood. Here, we identify novel pathway which astrocytes actively participate pre-synaptic autophagosomes. Using neurons derived human induced pluripotent stem cell (hiPSC) lines expressing fluorescent markers chimeric mouse models, demonstrate that autophagosomal vesicles are physically transferred to astrocytes, enhanced when suppressed. Autophagosome transfer does not require direct physical contact, but it Dynamin cholesterol-dependent endocytosis internalized ultimately fuse with astrocytic lysosomes. Our findings reveal previously unrecognized mechanism slow axonal retrograde transport their nearby astrocytes.

Language: Английский

Citations

1
Soma-centered control of synaptic autophagy by Rab39-regulated anterograde trafficking of Atg9 DOI Open Access
Ayse Kilic,

Dirk Vandekerkhove,

Sabine Kuenen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein organelle turnover. In this work, we report a soma-centered mechanism that regulates autophagy-driven turnover at distant presynaptic in Drosophila. We show system is regulated by Rab39, whose human homolog mutated Parkinson's disease. Although Rab39 localized soma, its loss of function causes increased autophagy terminals, resulting faster synaptic neurodegeneration. Using large-scale unbiased genetic modifier screen, identified genes encoding cytoskeletal axonal organizing proteins, including Shortstop (Shot), as suppressors autophagy. demonstrate controls Shot- Unc104/KIF1a-mediated transport autophagy-related Atg9 vesicles synapses. Under starvation conditions, soma shifts localization endosomes lysosomes, thereby controlling availability for trafficking Our findings indicate Rab39-mediated orchestrates cross-compartmental abundance

Language: Английский

Citations

1
Endosomal sorting protein SNX4 limits synaptic vesicle docking and release DOI Creative Commons

Josse Poppinga,

Nicholas Barrett, L. Niels Cornelisse

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Dec. 19, 2024

Sorting nexin 4 (SNX4) is an evolutionary conserved organizer of membrane recycling. In neurons, SNX4 accumulates in synapses, but how affects synapse function remains unknown. We generated a conditional knock-out mouse model and report that cKO synapses show enhanced neurotransmission during train stimulation, while the first evoked EPSC was normal. depletion did not affect vesicle recycling, basic autophagic flux, or levels localization SNARE-protein VAMP2/synaptobrevin-2. However, affected ultrastructure: increase docked synaptic vesicles at active zone, overall number normal, decreased zone length. These effects together lead to substantially increased density per release site. conclusion, negative regulator docking release. findings suggest role for recruitment zone.

Language: Английский

Citations

1
Turnover of synaptic adhesion molecules DOI

Melinda Nabavi,

P. Robin Hiesinger

Molecular and Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 124, P. 103816 - 103816

Published: Jan. 14, 2023

Language: Английский

Citations

3
Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling DOI Open Access
Melina Overhoff, Frederik Tellkamp, Simon Heß

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Feb. 11, 2022

Abstract Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show the protein AuTophaGy 5 (ATG5) functions in neurons to regulate cAMP-dependent kinase A (PKA)-mediated phosphorylation of synapse-confined proteome. This function ATG5 independent bulk turnover synaptic proteins requires targeting PKA inhibitory R1 subunits autophagosomes. Neuronal loss causes accumulation R1, which sequesters catalytic subunit diminishes cAMP/PKA-dependent postsynaptic cytoskeletal mediating AMPAR trafficking. Glutamatergic neurons-confined deletion augments AMPAR-dependent excitatory neurotransmission appearance spontaneous recurrent seizures mice. Our findings identify novel role regulating signaling at glutamatergic synapses suggest as target for restoration neurodegenerative conditions with dysfunction.

Language: Английский

Citations

4