The 2004 Nobel Prize in chemistry for the discovery of protein ubiquitination has led to the recognition of cellular proteolysis as a central area of research in biology. Eukaryotic proteins targeted for degradation by this pathway are first 'tagged' by multimers of a protein known as ubiquitin and are later proteolyzed by a giant enzyme known as the proteasome. This article recounts the key observations that led to the discovery of ubiquitin-proteasome system (UPS). In addition, different aspects of proteasome biology are highlighted. Finally, some key roles of the UPS in different areas of biology and the use of inhibitors of this pathway as possible drug targets are discussed.
LMP2, LMP7, and MECL are interferon γ–inducible catalytic subunits of vertebrate 20S proteasomes, which can replace constitutive catalytic subunits (delta, X, and Z, respectively) during proteasome biogenesis. We demonstrate that MECL requires LMP2 for efficient incorporation into preproteasomes, and preproteasomes containing LMP2 and MECL require LMP7 for efficient maturation. The latter effect depends on the presequence of LMP7, but not on LMP7 catalytic activity. This cooperative mechanism favors the assembly of homogeneous “immunoproteasomes” containing all three inducible subunits, suggesting that these subunits act in concert to enhance proteasomal generation of major histocompatibility complex class I–binding peptides.
The assembly of individual proteasome subunits into catalytically active mammalian 20S proteasomes is not well understood. Using subunit‐specific antibodies, we characterized both precursor and mature proteasome complexes. Antibodies to PSMA4 (C9) immunoprecipitated complexes composed of α, precursor β and processed β subunits. However, antibodies to PSMA3 (C8) and PSMB9 (LMP2) immunoprecipitated complexes made up of α and precursor β but no processed β subunits. These complexes possess short half‐lives, are enzymatically inactive and their molecular weight is ∼300 kDa. Radioactivity chases from these complexes into mature, long‐lived ∼700 kDa proteasomes. Therefore, these structures represent precursor proteasomes and are probably made up of two rings: one containing α subunits and the other, precursor β subunits. The assembly of precursor proteasomes occurs in at least two stages, with precursor β subunits PSMB2 (C7‐I), PSMB3 (C10‐II), PSMB7 (Z), PSMB9 (LMP2) and PSMB10 (LMP10) being incorporated before others [PSMB1 (C5), PSMB6 (delta), and PSMB8 (LMP7)]. Proteasome maturation (processing of the β subunits and juxtaposition of the two β rings) is accompanied by conformational changes in the (outer) α rings, and may be inefficient. Finally, interferon‐γ had no significant effect on the half‐lives or total amounts of precursor or mature proteasomes.
In the current era of functional surgery for movement disorders, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favoured target in the treatment of patients with dystonia. The results of 25 consecutive patients with medically intractable dystonia (12 with generalised dystonia, 7 with spasmodic torticollis, and 6 with other types of dystonia) treated with GPi stimulation are reported. Although comparisons were limited by differences in their respective neurological rating scales, chronic DBS benefited all groups, resulting in clear and progressive improvements in their condition. This study clearly demonstrates that DBS of the GPi provides amelioration of intractable dystonia.
We have studied the effects of stimulating the pedunculopontine nuclei through a fully implanted macroelectrode with a s.c. implantable pulse generator whose parameters can be programmed telemetrically, in a macaque before and after inducing Parkinsonian akinesia with MPTP. Our results show that in the normal monkey high frequency stimulation of the pedunculopontine nuclei reduces motor activity while low frequency stimulation increases it significantly over baseline. After making the monkey Parkinsonian with MPTP, unilateral low frequency stimulation of the pedunculopontine nuclei led to significant increases in activity. These results suggest that pedunculopontine nuclei stimulation could be clinically effective in treating advanced Parkinson's disease and other akinetic disorders.
In 15 patients with primary dystonia (six cervical and nine generalized dystonias) who were treated with bilateral chronic pallidal stimulation, we investigated the sensorimotor modulation of the oscillatory local field potentials (LFPs) recorded from the pallidal electrodes. We correlated these with the surface electromyograms in the affected muscles. The effects of involuntary, passive and voluntary movement and muscle-tendon vibration on frequency ranges of 0-3 Hz, theta (3-8 Hz), alpha (8-12 Hz), low (12-20 Hz) and high beta (20-30 Hz), and low (30-60 Hz) and high gamma (60-90 Hz) power were recorded and compared between cervical and generalized dystonia groups. Significant decreases in LFP synchronization at 8-20 Hz occurred during the sensory modulation produced by voluntary or passive movement or vibration. Voluntary movement also caused increased gamma band activity (30-90 Hz). Dystonic involuntary muscle spasms were specifically associated with increased theta, alpha and low beta (3-18 Hz). Furthermore, the increase in the frequency range of 3-20 Hz correlated with the strength of the muscle spasms and preceded them by approximately 320 ms. Differences in modulation of pallidal oscillation between cervical and generalized dystonias were also revealed. This study yields new insights into the pathophysiological mechanisms of primary dystonias and their treatment using pallidal deep brain stimulation.
Deep brain stimulation for the alleviation of movement disorders and pain is now an established therapy. However, very little has been published on the topic of hardware failure in the treatment of such conditions irrespective of clinical outcome. Such device-related problems lead to significant patient morbidity and increased cost of therapy in the form of prolonged antibiotics, in-patient hospitalization, repeat surgery, and device replacement. We report a prospective review of our experience at the Radcliffe Infirmary Oxford from the period of April 1998 to March 2001. Overall there is a 20% rate of hardware-related problems in this series, which falls between the 7% and 65% rates reported by other groups. The majority of these failures occurred early on in the series, and numbers declined with experience. Some of the problems may be idiosyncratic to the methodology of individual groups.
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