The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression
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Evaluation Summary:
In the study presented here, the authors used the fruitfly Drosophila melanogaster to identify a new molecular regulator - the E3 ubiquitin ligase Thin - of presynaptic homeostatic plasticity (PHP), a process where synaptic signaling between motorneurons and muscle cells is dynamically adapted to compensate exogenously imposed changes in synapse strength. Based on a very substantial set of high quality data, the authors propose that Thin functions presynaptically during PHP, that presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready synaptic vesicles, and that Thin controls transmitter release by regulating Dysbindin, a schizophrenia-susceptibility gene required for PHP. The authors' conclusion is that Thin links protein-degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release. The major claims of the paper are well supported by the data, but alternative hypotheses cannot yet be unequivocally excluded.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)
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Abstract
Synaptic proteins and synaptic transmission are under homeostatic control, but the relationship between these two processes remains enigmatic. Here, we systematically investigated the role of E3 ubiquitin ligases, key regulators of protein degradation-mediated proteostasis, in presynaptic homeostatic plasticity (PHP). An electrophysiology-based genetic screen of 157 E3 ligase-encoding genes at the Drosophila neuromuscular junction identified thin , an ortholog of human tripartite motif-containing 32 ( TRIM32 ), a gene implicated in several neurological disorders, including autism spectrum disorder and schizophrenia. We demonstrate that thin functions presynaptically during rapid and sustained PHP. Presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready vesicles, largely independent of gross morphological defects. We provide genetic evidence that thin controls release through dysbindin , a schizophrenia-susceptibility gene required for PHP. Thin and Dysbindin localize in proximity within presynaptic boutons, and Thin degrades Dysbindin in vitro. Thus, the E3 ligase Thin links protein degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release.
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Evaluation Summary:
In the study presented here, the authors used the fruitfly Drosophila melanogaster to identify a new molecular regulator - the E3 ubiquitin ligase Thin - of presynaptic homeostatic plasticity (PHP), a process where synaptic signaling between motorneurons and muscle cells is dynamically adapted to compensate exogenously imposed changes in synapse strength. Based on a very substantial set of high quality data, the authors propose that Thin functions presynaptically during PHP, that presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready synaptic vesicles, and that Thin controls transmitter release by regulating Dysbindin, a schizophrenia-susceptibility gene required for PHP. The authors' conclusion is that Thin links protein-degradation-dependent …
Evaluation Summary:
In the study presented here, the authors used the fruitfly Drosophila melanogaster to identify a new molecular regulator - the E3 ubiquitin ligase Thin - of presynaptic homeostatic plasticity (PHP), a process where synaptic signaling between motorneurons and muscle cells is dynamically adapted to compensate exogenously imposed changes in synapse strength. Based on a very substantial set of high quality data, the authors propose that Thin functions presynaptically during PHP, that presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready synaptic vesicles, and that Thin controls transmitter release by regulating Dysbindin, a schizophrenia-susceptibility gene required for PHP. The authors' conclusion is that Thin links protein-degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release. The major claims of the paper are well supported by the data, but alternative hypotheses cannot yet be unequivocally excluded.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)
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Joint Public Review:
The authors investigated presynaptic homeostatic plasticity (PHP) at the glutamatergic larval Drosophila neuromuscular junction (NMJ). In this facet of synaptic plasticity, the presynapse increases neurotransmitter release to compensate for diminished postsynaptic sensitivity. To study functional pathways and to identify new molecular components of PHP, the authors carried out a large, electrophysiology-based genetic screen focusing on E3 ubiquitin ligases - key elements of the major cellular protein degradation pathway. This genetic screen, which forms the backbone of the paper, generated an extensive data set encompassing 180 genotypes. This is an impressive achievement. The authors find that the E3 ligase Thin suppresses glutamate release by downregulating Dysbindin, a transmitter release-promoting presynaptic …
Joint Public Review:
The authors investigated presynaptic homeostatic plasticity (PHP) at the glutamatergic larval Drosophila neuromuscular junction (NMJ). In this facet of synaptic plasticity, the presynapse increases neurotransmitter release to compensate for diminished postsynaptic sensitivity. To study functional pathways and to identify new molecular components of PHP, the authors carried out a large, electrophysiology-based genetic screen focusing on E3 ubiquitin ligases - key elements of the major cellular protein degradation pathway. This genetic screen, which forms the backbone of the paper, generated an extensive data set encompassing 180 genotypes. This is an impressive achievement. The authors find that the E3 ligase Thin suppresses glutamate release by downregulating Dysbindin, a transmitter release-promoting presynaptic protein. Based on the experimental data, a model is put forward according to which PHP arises by relieving Dysbindin of Thin-dependent ubiquitination and degradation.
This is a strong paper that adds a highly interesting feature to our understanding of the molecular mechanisms that control synaptic strength. On the other hand, two key aspects of the major conclusions remain equivocal, requiring rectification: (i) A precise interpretation of the morphological phenotypes and the corresponding molecular processes controlled by Thin is not yet fully possible. (ii) Some aspects of the Thin-Dysbindin interplay remain unclear.
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