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1.
J Cell Biol ; 220(5)2021 05 03.
Article in English | MEDLINE | ID: mdl-33683284

ABSTRACT

Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Endosomes/metabolism , Endosomes/physiology , Neurons/metabolism , Neurons/physiology , Post-Synaptic Density/metabolism , Post-Synaptic Density/physiology , Amyotrophic Lateral Sclerosis/genetics , Animals , Biological Transport/physiology , Cell Death/genetics , Cell Survival/genetics , Cells, Cultured , Drosophila/genetics , Drosophila/metabolism , Drosophila/physiology , Endosomes/genetics , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Mutation/genetics , Phenotype , Post-Synaptic Density/genetics , rab5 GTP-Binding Proteins/genetics , rab5 GTP-Binding Proteins/metabolism
2.
Elife ; 92020 12 10.
Article in English | MEDLINE | ID: mdl-33300871

ABSTRACT

Synaptic vesicle (SV) endocytosis is coupled to exocytosis to maintain SV pool size and thus neurotransmitter release. Intense stimulation induces activity-dependent bulk endocytosis (ADBE) to recapture large quantities of SV constituents in large endosomes from which SVs reform. How these consecutive processes are spatiotemporally coordinated remains unknown. Here, we show that Flower Ca2+ channel-dependent phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) compartmentalization governs control of these processes in Drosophila. Strong stimuli trigger PI(4,5)P2 microdomain formation at periactive zones. Upon exocytosis, Flower translocates from SVs to periactive zones, where it increases PI(4,5)P2 levels via Ca2+ influxes. Remarkably, PI(4,5)P2 directly enhances Flower channel activity, thereby establishing a positive feedback loop for PI(4,5)P2 microdomain compartmentalization. PI(4,5)P2 microdomains drive ADBE and SV reformation from bulk endosomes. PI(4,5)P2 further retrieves Flower to bulk endosomes, terminating endocytosis. We propose that the interplay between Flower and PI(4,5)P2 is the crucial spatiotemporal cue that couples exocytosis to ADBE and subsequent SV reformation.


Subject(s)
Calcium Channels/metabolism , Drosophila Proteins/metabolism , Endocytosis/physiology , Phosphatidylinositol Phosphates/metabolism , Synaptic Vesicles/metabolism , Animals , Drosophila , Feedback, Physiological/physiology , Neuromuscular Junction/metabolism , Presynaptic Terminals/metabolism , Synaptic Transmission/physiology
3.
Cell Rep ; 33(4): 108310, 2020 10 27.
Article in English | MEDLINE | ID: mdl-33113375

ABSTRACT

Neuromuscular junctions (NMJs) govern efficient neuronal communication with muscle cells, relying on proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to NMJ development remains unclear. In this study, we reveal that dynamin-2 (Dyn2) is involved in postsynaptic development of NMJs. Mutations of Dyn2 have been linked to human muscular disorder and centronuclear myopathy (CNM), as well as featured with muscle atrophy and defective NMJs, yet the function of Dyn2 at the postsynaptic membrane is largely unknown. We demonstrate that Dyn2 is enriched at the postsynaptic membrane and regulates NMJ development via actin remodeling. Dyn2 functions as an actin-bundling GTPase to regulate podosome turnover and cytoskeletal organization of the postsynaptic apparatus, and CNM-Dyn2 mutations display abnormal actin remodeling and electrophysiological activity of fly NMJs. Altogether, Dyn2 primarily regulates actin cytoskeleton remodeling and NMJ morphogenesis at the postsynaptic membrane, which is distinct from its endocytosis regulatory role at the presynaptic membrane.


Subject(s)
Cytoskeleton/physiology , Dynamin II/metabolism , Neuromuscular Junction/growth & development , Humans
4.
Elife ; 82019 07 18.
Article in English | MEDLINE | ID: mdl-31318331

ABSTRACT

Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS, thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.


Subject(s)
Drosophila melanogaster/physiology , Feedback, Physiological , Glutamic Acid/toxicity , Motor Neurons/physiology , Neurotoxins/toxicity , Reactive Oxygen Species/metabolism , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Cholinergic Neurons/drug effects , Cholinergic Neurons/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/drug effects , Interneurons/drug effects , Interneurons/metabolism , MAP Kinase Signaling System/drug effects , Motor Neurons/drug effects , Mutation/genetics , Neuroglia/drug effects , Neuroglia/metabolism , Neuromuscular Junction/drug effects , Neuromuscular Junction/metabolism , Oxidative Stress/drug effects
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