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