Deneddylating enzyme SENP8 regulates neuronal development

• Published in: Journal of neurochemistry Vol. 165; no. 3; pp. 348 - 361
• Main Authors: Song, Jae‐man, Kang, Minji, Lee, Seungha, Kim, Jungho, Park, Sunha, Park, Da‐ha, Lee, Sanghyeon, Suh, Young Ho
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2023
• Subjects: Actin; Animals; Axonogenesis; Clustering; Disks Large Homolog 4 Protein; Endopeptidases - metabolism; Enzymes; Glutamic acid receptors (metabotropic); Lysine; Maturation; metabotropic glutamate receptor 7; neurite outgrowth; Neurodevelopmental disorders; Neurogenesis; Neurons; Postsynaptic density; postsynaptic density protein 95; Proteins; Rats; Substrates; SUMO Peptidase Family Member, NEDD8 Specific; synapse maturation; Synapses - physiology; Synaptic clustering; Synaptogenesis; Therapeutic targets; Ubiquitination; Wnt protein; SUMO Peptidase Family Member, NEDD8 Specific; synapse maturation; neurite outgrowth; neurodevelopmental disorders; metabotropic glutamate receptor 7; postsynaptic density protein 95
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15797

Neddylation is a cellular process in which the neural precursor cell expressed, developmentally down‐regulated 8 (NEDD8) is conjugated to the lysine residue of target proteins via serial enzymatic cascades. Recently, it has been demonstrated that neddylation is required for synaptic clustering of metabotropic glutamate receptor 7 (mGlu7) and postsynaptic density protein 95 (PSD‐95), and the inhibition of neddylation impairs neurite outgrowth and excitatory synaptic maturation. Similar to the balanced role of deubiquitylating enzymes (DUBs) in the ubiquitination process, we hypothesized that deneddylating enzymes can regulate neuronal development by counteracting the process of neddylation. We find that the SUMO peptidase family member, NEDD8 specific (SENP8) acts as a key neuronal deneddylase targeting the global neuronal substrates in primary rat cultured neurons. We demonstrate that SENP8 expression levels are developmentally regulated, peaking around the first postnatal week and gradually diminishing in mature brain and neurons. We find that SENP8 negatively regulates neurite outgrowth through multiple pathways, including actin dynamics, Wnt/β‐catenin signaling, and autophagic processes. Alterations in neurite outgrowth by SENP8 subsequently result in the impairment of excitatory synapse maturation. Our data indicate that SENP8 plays an essential role in neuronal development and is a promising therapeutic target for neurodevelopmental disorders. We discovered that SUMO peptidase family member, NEDD8 specific (SENP8) is a key deneddylase acting in the neurons. SENP8 deneddylates substrates including metabotropic glutamate receptor 7 (mGlu7) and postsynaptic density protein 95 (PSD‐95). SENP8 expression is developmentally regulated, peaks in the first postnatal week, and gradually declines in the mature brain. SENP8 negatively regulates neurite outgrowth via three pathways: actin dynamics, Wnt/β‐catenin signaling, and autophagic processes. Inhibition of neurite outgrowth by SENP8 impairs excitatory synapse maturation. We propose SENP8 as a promising therapeutic target for neurodevelopmental disorders.