Ubiquitin ligase signalling networks shape presynaptic development, function and disease

Ubiquitin ligases are important regulators of nervous system development, function and disease. To date, numerous ubiquitin ligases have been discovered that regulate presynaptic biology. Here, we discuss recent findings on presynaptic ubiquitin ligases that include members from the three major ubiquitin ligase classes: RING, RBR and HECT. Several themes emerge based on findings across a range of model systems. A cadre of ubiquitin ligases is required presynaptically to orchestrate development and transmission at synapses. Multiple ubiquitin ligases deploy both enzymatic and non‐enzymatic mechanisms, and act as hubs for signalling networks at the synapse. Both excitatory and inhibitory presynaptic terminals are influenced by ligase activity. Finally, there are several neurodevelopmental disorders and neurodegenerative diseases associated with presynaptic ubiquitin ligases. These findings highlight the growing prominence and biomedical relevance of the presynaptic ubiquitin ligase network.

• Publication year

  2024

• Venue

  Journal of Physiology

• Publication date

  2024-10-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1113/JP286469PMID 39360902PMCID PMC11965430
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

  2024cited by this paper
• Presynaptic Ube3a E3 ligase promotes synapse elimination through down-regulation of BMP signaling

  2023cited by this paper
• PHYSIOLOGICAL FUNCTIONS OF THE UBIQUITIN LIGASES NEDD4-1 AND NEDD4-2.

  2023cited by this paper
• Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

  2023cited by this paper
• Abstract 1447: Ubiquitin ligase activity inhibits Cdk5 to control axon termination

  2023cited by this paper
• Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.

  2023cited by this paper
• Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

  2022influential reference
• An atypical ubiquitin ligase at the heart of neural development and programmed axon degeneration

  2022cited by this paper
• Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.

  2022cited by this paper
• PINK1-PRKN mediated mitophagy: differences between in vitro and in vivo models

  2022cited by this paper
• Role of post-translational modifications on the alpha-synuclein aggregation-related pathogenesis of Parkinson’s disease

  2022cited by this paper
• The HERC proteins and the nervous system.

  2021cited by this paper
• The role of E3 ubiquitin ligases in synapse function in the healthy and diseased brain.

  2021cited by this paper
• The ubiquitin ligase Ariadne-1 regulates neurotransmitter release via ubiquitination of NSF

  2021influential reference
• The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin

  2021cited by this paper
• Cullin-RING Ubiquitin Ligase Regulatory Circuits: a Quarter Century Beyond the F-box Hypothesis.

  2021cited by this paper
• The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression

  2021cited by this paper
• Mini-review: Synaptojanin 1 and its implications in membrane trafficking

  2021cited by this paper
• OUP accepted manuscript

  2021cited by this paper
• The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc

  2020cited by this paper
• Synapse development and maturation at the drosophila neuromuscular junction

  2020influential reference
• Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability

  2020cited by this paper
• BSN (bassoon) and PRKN/parkin in concert control presynaptic vesicle autophagy

  2020cited by this paper
• The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

  2020cited by this paper
• De novo variants in SIAH1, encoding an E3 ubiquitin ligase, are associated with developmental delay, hypotonia and dysmorphic features

  2020cited by this paper
• Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice

  2020cited by this paper
• Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease

  2020cited by this paper
• The Autism and Angelman Syndrome Protein Ube3A/E6AP: The Gene, E3 Ligase Ubiquitination Targets and Neurobiological Functions

  2019cited by this paper
• Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor

  2019cited by this paper
• Autophagy is inhibited by ubiquitin ligase activity in the nervous system

  2019cited by this paper
• E3 ubiquitin ligases LNX1 and LNX2 are major regulators of the presynaptic glycine transporter GlyT2

  2019influential reference
• The ubiquitin ligase UBE3B, disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK

  2019cited by this paper
• A complex containing the O-GlcNAc transferase OGT-1 and the ubiquitin ligase EEL-1 regulates GABA neuron function

  2019influential reference
• Synapse maintenance is impacted by ATAT-2 tubulin acetyltransferase activity and the RPM-1 signaling hub

  2019cited by this paper
• The E3 ligase Highwire promotes synaptic transmission by targeting the NAD‐synthesizing enzyme dNmnat

  2019cited by this paper
• Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity

  2018cited by this paper
• Enhanced Transmission at the Calyx of Held Synapse in a Mouse Model for Angelman Syndrome

  2018cited by this paper
• Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles

  2018cited by this paper
• Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting

  2018influential reference
• PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

  2018cited by this paper
• Regulation of SH3PX1 by dNedd4-long at the Drosophila neuromuscular junction

  2018cited by this paper
• Subcellular organization of UBE3A in human cerebral cortex

  2018cited by this paper
• The synaptic function of parkin

  2017cited by this paper
• Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice

  2017cited by this paper
• HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

  2017cited by this paper
• Mutation of the HERC 1 Ubiquitin Ligase Impairs Associative Learning in the Lateral Amygdala

  2017cited by this paper
• Bassoon Controls Presynaptic Autophagy through Atg5.

  2017cited by this paper
• Axon Termination, Pruning, and Synaptogenesis in the Giant Fiber System of Drosophila melanogaster Is Promoted by Highwire

  2017cited by this paper
• RPM-1 regulates axon termination by affecting growth cone collapse and microtubule stability

  2017cited by this paper
• Identification and characterization of a missense mutation in the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase gene that segregates with X-linked intellectual disability

  2017cited by this paper
• Ubiquitin Ligases: Structure, Function, and Regulation.

  2017cited by this paper
• Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with X-linked intellectual disability

  2017cited by this paper
• Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors

  2017cited by this paper
• Subcellular organization of UBE3A in neurons

  2017cited by this paper
• Proteomic analysis reveals novel ligands and substrates for LNX1 E3 ubiquitin ligase

  2017cited by this paper
• The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.

  2017influential reference
• Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila

  2017cited by this paper
• Parkin Modulates Endosomal Organization and Function of the Endo-Lysosomal Pathway

  2016cited by this paper
• Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila

  2016influential reference
• The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration

  2016cited by this paper
• HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study

  2016influential reference
• The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction

  2015cited by this paper
• Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability

  2015cited by this paper
• Pathological axonal death through a MAPK cascade that triggers a local energy deficit.

  2015cited by this paper
• Homeostatic control of presynaptic neurotransmitter release.

  2015cited by this paper
• A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

  2015influential reference
• Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

  2014cited by this paper
• Identification of a Peptide Inhibitor of the RPM-1·FSN-1 Ubiquitin Ligase Complex*

  2014cited by this paper
• Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome

  2013cited by this paper
• Development and plasticity of the Drosophila larval neuromuscular junction

  2013cited by this paper
• The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction.

  2013cited by this paper
• Spatial organization of ubiquitin ligase pathways orchestrates neuronal connectivity.

  2013cited by this paper
• Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation

  2013cited by this paper
• Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects.

  2012cited by this paper
• Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome.

  2012cited by this paper
• The E3 Ubiquitin Ligase Protein Associated with Myc (Pam) Regulates Mammalian/Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling in Vivo through N- and C-terminal Domains*

  2012cited by this paper
• The Highwire Ubiquitin Ligase Promotes Axonal Degeneration by Tuning Levels of Nmnat Protein

  2012influential reference
• Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes.

  2011cited by this paper
• Rare Copy Number Variation Discovery and Cross-Disorder Comparisons Identify Risk Genes for ADHD

  2011cited by this paper
• Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice

  2011cited by this paper
• EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation.

  2010cited by this paper
• The role of parkin in familial and sporadic Parkinson's disease

  2010cited by this paper
• Clinical and genetic aspects of Angelman syndrome

  2010cited by this paper
• Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development

  2009cited by this paper
• SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination.

  2009cited by this paper
• Abnormal development of the neuromuscular junction in Nedd4-deficient mice.

  2009cited by this paper
• The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration.

  2009cited by this paper
• A FAM21-containing WASH complex regulates retromer-dependent sorting.

  2009cited by this paper
• Physiological functions of the HECT family of ubiquitin ligases

  2009cited by this paper
• Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

  2009cited by this paper
• A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

  2009cited by this paper
• The genetics of hyperekplexia: more than startle!

  2008cited by this paper
• The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons.

  2007cited by this paper
• The active zone protein CAST directly associates with Ligand-of-Numb protein X.

  2007cited by this paper
• SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release.

  2007cited by this paper
• The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics.

  2007cited by this paper
• Highwire restrains synaptic growth by attenuating a MAP kinase signal.

  2006cited by this paper
• Regulation of Commissureless by the Ubiquitin Ligase DNedd4 Is Required for Neuromuscular Synaptogenesis in Drosophila melanogaster

  2006cited by this paper
• Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease

  2006cited by this paper
• Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development.

  2005cited by this paper

• No citing papers are available for this paper.