Rings, chains and ladders: ubiquitin goes to work in the neuron

https://doi.org/10.1016/j.pneurobio.2004.05.004Get rights and content

Abstract

Our understanding of neuronal cell biology in the last 10 years has exploded. In parallel, our grasp of basic cellular processes, such as protein synthesis and protein degradation has also grown exponentially. In this review, we provide an in-depth background to details of current knowledge of the Ub/proteasome pathway. We also provide examples of recent experiments in neurobiology that suggest a central role for targeted protein degradation by the Ub/proteasome pathway to ensure proper neuronal function. From the examples provided, it is clear the activity of the proteasome is required for neuronal pathfinding during development, regulation of synaptic branching and number, and synaptic plasticity. We conclude with a discussion of how defects in proteasome pathway function may lead to neuronal dysfunction, with specific emphasis on diseases characterized by the accumulation of ubiquitin (Ub)-positive inclusions. Our goal is to excite the expert neurobiologist to the myriad ways that specific neuronal functions could be regulated (or dysregulated) by mechanisms involving the Ub/proteasome pathway.

Introduction

The initial observation that led to the nomenclature for ubiquitin (Ub) could not have been more prescient. Not only is ubiquitin present in all eukaryotes, but it also appears to function in most cellular activities. Our view of the ubiquitin/proteasome pathway has evolved from that of a non-specific disposal mechanism, to what we now believe to be an exquisitely regulated choreographer of a multitude of diverse cellular functions. The first significant role for ubiquitin was discovered through studies of the cell cycle, primarily in yeast, sea urchins and surf clams (Minshull et al., 1989, Willems et al., 1996). Later, ubiquitin was shown to be a major player in DNA damage repair mechanisms (Jensen et al., 1995). During the 1980s interest in cell cycle progression and DNA damage repair were not the realm of neurobiologists, and the ubiquitin proteasome pathway had yet to emerge as a major player in the regulation of post-mitotic neuronal function. The earliest indication of a role for ubiquitin in neurons was revealed by studies of neurodegeneration in post-mortem brain using ubiquitin immunohistochemistry. Neurofibrillary tangles, cortical and midbrain Lewy bodies and spinal anterior horn inclusions were all identified and characterized (with regards to specific cell types distinguishing distinct diseases) using ubiquitin immunohistochemistry (Mayer, 2003). This work revealed that ubiquitin immunoreactivity in the post-mortem brains of patients diagnosed with neurological disorders was drastically increased and localized to intracellular inclusions (Mayer, 2003). Contrary to the humble beginnings in a remote corner of neuropathology, the last 5 years have revealed a spectacular diversity of functional roles for the Ub/proteasome pathway in neurons. We now know that the behavior of the neuronal growth cone during development (Murphey and Godenschwege, 2002), as well as the subtle alterations in synapses that lead to synaptic plasticity, learning and memory (Hegde and DiAntonio, 2002) depend on the ubiquitination and subsequent degradation of key proteins in these pathways. Finally, coming full circle, distinct mechanisms that underlie the formation of ubiquitinated inclusions in cells has been discovered (Johnston et al., 1998), and suggest that even the accumulation of undegradable protein relies upon a coordinated series of cellular events, whose disruption can have dire consequences. In this review, we examine the mechanics of the Ub/proteasome pathway, followed by the many roles of ubiquitin in neuronal function, and conclude with a discussion of the consequences of alterations in this pathway in human neurological disease (summarized in Table 1). This recent intersection of proteasome biology and neurobiology and our increased knowledge of the regulation of neuronal function by the ubiquitin/proteasome pathway, provide a glimpse of new directions for future work to understand the complex function of human brain in health and disease.

Section snippets

The ubiquitin/proteasome system of intracellular proteolysis

Like all things in nature, proteins have a life cycle. They are synthesized, serve a function, and are then degraded. The balance between synthesis and degradation governs protein stability, while the regulation of protein activity can be imparted by a number of post-translational events. Protein degradation provides the irrevocable method for eliminating a biochemical activity, and the Ub/proteasome proteolytic pathway plays a central role in mediating this effect. The 26S proteasome consists

Neurons and ubiquitin

Neurons are a post-mitotic, polarized cell type, with a very large surface area that relies heavily on cell surface proteins to respond to extracellular stimuli. During development, neurons grow through a complicated forest of factors and must find their way to their target destination by responding to extracellular cues via cell surface receptors. At their destination, the association of specific cell surface proteins between neurons generates communication structures called synapses. Synapses

Pathfinding of neurons during development

Neuronal growth in development is a complex process whereby the neuron is directed by a variety of diffusible and membrane bound stimuli that control the movement of the growth cone. This movement in response to stimuli relies in part upon a particular array of cell surface receptors, whose delivery to the cell surface can be controlled at many levels. A common mechanism for rapid cellular response to external stimuli is to affect the stability of a protein. The degradation of native proteins

Ubiquitin and neuronal disease

The formation and function of healthy synapses clearly depends on ubiquitin pathway activities. What happens when the proteasome pathway does not work? What does it actually mean to say that the ub/proteasome pathway is not working, or that proteasome activity is inhibited? Clearly, the timely degradation of SPAR by Snk is required to successfully accomplish activity-induced changes in synapses. Moreover, Ub/proteasome pathway activity is required for the development of LTP and LTD, and

References (293)

  • C. Buttner et al.

    Ubiquitination precedes internalization and proteolytic cleavage of plasma membrane-bound glycine receptors

    J. Biol. Chem.

    (2001)
  • T. Caldas et al.

    Chaperone properties of bacterial elongation factor EF-G and initiation factor IF2

    J. Biol. Chem.

    (2000)
  • D.S. Campbell et al.

    Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation

    Neuron

    (2001)
  • G. Carrard et al.

    Impairment of proteasome structure and function in aging

    Int. J. Biochem. Cell Biol.

    (2002)
  • R.W. Carrell et al.

    Conformational disease

    Lancet

    (1997)
  • P. Chen et al.

    Autocatalytic subunit processing couples active site formation in the 20S proteasome to completion of assembly

    Cell

    (1996)
  • P. Chen et al.

    Multiple ubiquitin-conjugating enzymes participate in the in vivo degradation of the yeast MATα2 repressor

    Cell

    (1993)
  • Z.J. Chen et al.

    Site-specific phosphorylation of IκBαby a novel ubiquitination-dependent protein kinase activity

    Cell

    (1996)
  • T.R. Clandinin et al.

    Making connections in the fly visual system

    Neuron

    (2002)
  • M. Colledge et al.

    Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression

    Neuron

    (2003)
  • C.M. Crews

    Feeding the machine: mechanisms of proteasome-catalyzed degradation of ubiquitinated proteins

    Curr. Opin. Chem. Biol.

    (2003)
  • C.J. Cummings et al.

    Neuron

    (1999)
  • C.J. Cummings et al.

    Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice

    Neuron

    (1999)
  • J.R. de la Torre et al.

    Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC

    Neuron

    (1997)
  • J.M. Desterro et al.

    SUMO-1 modification of IκBαinhibits NF-κBactivation

    Mol. Cell

    (1998)
  • Q. Deveraux et al.

    A 26S protease subunit that binds ubiquitin conjugates

    J. Biol. Chem.

    (1994)
  • S. Fang et al.

    Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53

    J. Biol. Chem.

    (2000)
  • J. Fergusson et al.

    Pathological lesions of Alzheimer’s disease and dementia with Lewy bodies brains exhibit immunoreactivity to an ATPase that is a regulatory subunit of the 26S proteasome

    Neurosci. Lett.

    (1996)
  • N. Finney et al.

    The cellular protein level of Parkin is regulated by its ubiquitin-like domain

    J. Biol. Chem.

    (2003)
  • H. Fu et al.

    Multiubiquitin chain binding and protein degradation are mediated by distinct domains within the 26S proteasome subunit Mcb1

    J. Biol. Chem.

    (1998)
  • A. Gautreau et al.

    Isolation and characterization of an aggresome determinant in the NF2 tumor suppressor

    J. Biol. Chem.

    (2003)
  • H. Gonen et al.

    Purification and characterization of a novel protein that is required for degradation of N-α-acetylated proteins by the ubiquitin system

    J. Biol. Chem.

    (1991)
  • S. Grigoryev et al.

    A mouse amidase specific for N-terminal asparagine

    J. Biol. Chem.

    (1996)
  • M. Harada et al.

    A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates

    Gastroenterology

    (2001)
  • S. Hatakeyama et al.

    U Box proteins as a new family of ubiquitin–protein ligases

    J. Biol. Chem.

    (2001)
  • A.N. Hegde et al.

    Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia

    Cell

    (1997)
  • C. Hirsch et al.

    Intracellular targeting of the proteasome

    Trends Cell Biol.

    (2000)
  • N. Hishikawa et al.

    Dorfin localizes to the ubiquitylated inclusions in Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis

    Am. J. Pathol.

    (2003)
  • K. Hofmann et al.

    The UBA domain: a sequence motif present in multiple enzyme classes of the ubiquitination pathway

    Trends Bio. Sci.

    (1996)
  • K. Hofmann et al.

    A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems

    Trends Biochem. Sci.

    (2001)
  • M. Aguilera et al.

    Ariadne-1: a vital Drosophila gene is required in development and defines a new conserved family of ring-finger proteins

    Genetics

    (2000)
  • F.J. Ahmad et al.

    Microtubules released from the neuronal centrosome are transported into the axon

    J. Cell Sci.

    (1995)
  • P.W. Baas

    Neuronal polarity: microtubules strike back

    Nat. Cell Biol.

    (2002)
  • M. Baba et al.

    Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies

    Am. J. Pathol.

    (1998)
  • N.W. Bays et al.

    Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation

    Nat. Cell Biol.

    (2001)
  • R.E. Beal et al.

    The hydrophobic effect contributes to polyubiquitin chain recognition

    Biochemistry

    (1998)
  • F.K. Bedford et al.

    GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1

    Nat. Neurosci.

    (2001)
  • N.F. Bence et al.

    Impairment of the ubiquitin-proteasome system by protein aggregation

    Science

    (2001)
  • B.L. Bertolaet et al.

    UBA domains of DNA damage-inducible proteins interact with ubiquitin

    Nat. Struct. Biol.

    (2001)
  • S. Biggins et al.

    Yeast ubiquitin-like genes are involved in duplication of the microtubule organizing center

    J. Cell Biol.

    (1996)
  • Cited by (23)

    • The elimination of accumulated and aggregated proteins: A role for aggrephagy in neurodegeneration

      2011, Neurobiology of Disease
      Citation Excerpt :

      It has been proposed that the aggresome is a protective structure, formed to sequester proteins that cannot be degraded by the proteasome and packaged for degradation by autophagy (Johnston et al., 1998; Kopito, 2000). Although studies in heterologous systems clearly demonstrate that disease-causing proteins become packaged in this manner (Iwata et al., 2005; Johnston and Madura, 2004; Waelter et al., 2001; Wong et al., 2008), this may not be the case for neurons. For instance, neuronal cytoplasmic inclusions (NCIs) are ubiquitinated but rarely vimentin-positive, possibly because vimentin is expressed predominantly in immature neurons and become replaced by neurofilaments (NFs) as neurons mature (Bennett et al., 1981; Cochard and Paulin, 1984).

    • Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V

      2009, Biophysical Journal
      Citation Excerpt :

      The unfolding and aggregation pathway of the protein involves the dissociation of the dimer and loss of metal binding, followed by the subsequent oligomeric assembly of the protein (12–14). It is also possible that the aggregates are favored when the amount of misfolded protein reaches a point where the ubiquitin proteolytic machinery becomes unable to handle the load (15,16). Although the aforementioned experimental approaches have been enlightening, there are other opportunities to investigate the effects of mutation on the protein.

    View all citing articles on Scopus
    View full text