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0031-6997/07/5901-14-39$7.00
Pharmacol Rev 59:14-39, 2007

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Emerging Roles for Ubiquitin and Protein Degradation in Neuronal Function

Jason J. Yi and Michael D. Ehlers

Program in Cell and Molecular Biology (J.J.Y., M.D.E.), Department of Pharmacology and Cancer Biology (J.J.Y., M.D.E.), Department of Neurobiology (M.D.E.), and Howard Hughes Medical Institute (M.D.E.), Duke University Medical Center, Durham, North Carolina

Abstract
I. Introduction
    A. Components of the Ubiquitin-Proteasome System
        1. Ubiquitin, E1, and E2.
        2. E3 Ubiquitin Ligases.
        3. The 26S Proteasome.
        4. Deubiquitinating Enzymes.
        5. Ubiquitin-Proteasome System Adaptor Proteins.
    B. Endoplasmic Reticulum-Associated Degradation
    C. Monoubiquitination and the Endocytic Pathway
II. The Ubiquitin-Proteasome System in Neuronal Function
    A. Neuronal Development
        1. Axon Growth, Steering, and Pruning.
        2. Synapse Formation and Elimination.
    B. Presynaptic Function
    C. Postsynaptic Plasticity
        1. The Ubiquitin-Proteasome System in Long-Term Potentiation.
        2. Ubiquitin-Proteasome System-Dependent Remodeling of the Postsynaptic Density.
    D. Ubiquitin and Postsynaptic Receptor Trafficking
        1. Glutamate Receptor Regulation in Caenorhabditis elegans.
        2. Glutamate Receptor Regulation in Mammals.
        3. Trafficking of GABA and Acetylcholine Receptors.
III. The Ubiquitin-Proteasome System in Neurological Disease
    A. Ubiquitin-Proteasome System-Linked Animal Models for Neurodegeneration
    B. Spinocerebellar Ataxia
    C. Parkinson's Disease
        1. Ubiquitin C-Terminal Hydrolase-L1 in Parkinson's Disease.
        2. Parkin.
    D. Neurodevelopmental Disorders: Angelman Syndrome
IV. Conclusions and Perspectives
Alterations in cellular structure and synapse composition are central to proper nervous system function. Recent work has identified the ubiquitin-proteasome system (UPS) as a key regulator of neuronal biology. The UPS is essential for the growth and development of immature neurons and is a criticalmediator of synaptic adaptability in mature neurons. Furthermore, proteinaceous deposits that accumulate in diverse neurodegenerative disorders are enriched in components of the UPS, suggesting that UPS dysfunction may be pivotal for pathogenesis. Here, we summarize existing knowledge about the role of the UPS in brain function, highlighting recent work delineating its importance in neuronal development, plasticity, and degeneration.

Address correspondence to: Dr. Michael D. Ehlers, HHMI, Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, NC 27710. E-mail: ehlers{at}neuro.duke.edu




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