Review article
Proteasomes and proteasome inhibition in the central nervous system

https://doi.org/10.1016/S0891-5849(01)00635-9Get rights and content

Abstract

Although the proteasome is responsible for the majority of intracellular protein degradation, and has been demonstrated to play a pivotal role in a diverse array of cellular activities, the role of the proteasome in the central nervous system is only beginning to be elucidated. Recent studies have demonstrated that proteasome inhibition occurs in numerous neurodegenerative conditions, and that proteasome inhibition is sufficient to induce neuron death, elevate intracellular levels of protein oxidation, and increase neural vulnerability to subsequent injury. The focus of this review is to describe what is currently known about proteasome biology in the central nervous system and to discuss the possible role of proteasome inhibition in the neurodegenerative process.

Introduction

Since the initial discovery and characterization of the multicatalytic proteasome complex approximately 20 years ago, tremendous progress has been made in our understanding of proteasome biology. Studies have now elucidated the primary structure of the proteasome complex, revealed a continually expanding repertoire of proteasome substrates, and elucidated a necessary role for proteasome activity in a wide range of cellular functions ranging from cell division to antigen presentation. In particular, the proteasome has emerged as an important secondary defense against oxidative stress, degrading oxidized and damaged proteins, and thus preventing their accumulation. It is therefore not surprising that several excellent reviews on the proteasome and proteasome biology are currently available. However, in spite of the tremendous progress made in proteasome research, the characterization of proteasome activity, proteasome expression, and proteasome function in the central nervous system (CNS) is poorly defined. The focus of this review is to provide a current review of what is known about the proteasome in the CNS, and describe the possible implications for proteasome inhibition in neurodegenerative disorders.

The proteasome is a large multicatalytic protease, that is present in all eukaryotic cells, and is responsible for the majority of intracellular proteolysis [1], [2], [3], [4], [5], [6], [7], [8], [9]. A growing list of proteasome substrates has been identified [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], and contains numerous proteins of direct importance in neurophysiological and neuropathological processes (Table 1). The core proteasome complex consists of a barrel-shaped structure, which is referred to as the 20S proteasome, which is comprised of 28 α- and β-subunits. The individual α- and β-subunits are arranged in four separate rings, with each ring consisting of either seven α- or seven β-subunits. The β-subunits comprise the two inner rings of the 20S proteasome, with the outer rings comprised of α-subunits. The proteasome proteolytic sites are located on individual β-subunits, with each proteolytic site directed towards the inner core of the barrel-shaped proteasome complex. Proteasome proteolytic activity can be distinguished from the majority of lysosomal-dependent proteolysis based on the fact that it occurs at neutral pH and does not require calcium or organelle compartmentalization. Additionally, although the proteasome was initially characterized for its role in ATP- and ubiquitin-dependent proteolysis, numerous studies have now clearly established that there is a significant amount of ATP- and ubiquitin-independent forms of proteasome activity [2], [3], [4].

The proteasome possesses multiple endopeptidase activities, the best characterized of which are the chymotrypsin-like, trypsin-like, and postglutamyl peptidase activities. Each proteasome proteolytic activity functions in a sequential manner to generate a variety of peptide products. The length, and type of peptides generated by the proteasome, is dictated by proteasome subunit composition and the spacing between the individual proteolytic sites. For example, individual β-subunits can be responsible for mediating either chymotrypsin-like, trypsin-like, or postglutamyl peptidase activity. The spacing of these β-subunits can be directly affected by 20S proteasome stability, or by the size of individual β-subunits. The α-subunits play important roles in maintaining 20S proteasome stability and providing scaffolding for 20S proteasome binding proteins, with both of these processes directly effecting overall proteasome activity. Over 15 different genes have been demonstrated to encode for individual α- and β-subunits [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], although the expression of each of these genes in the CNS is poorly defined (Table 2). The large number of proteasome subunit genes suggests that the proteasome complex may undergo numerous compositional changes, with multiple α- and β-subunits being interchanged within the cells of the CNS in order to address the specific proteolytic needs of a given cellular condition. Consistent with such events occurring in the CNS, studies in microglial cells have demonstrated that the composition of the proteasome is dramatically altered in response to the application of inflammatory agents [62], [63], with additional studies in non-CNS cell types providing further support for the idea that proteasome composition can be altered to address specific proteolytic needs [63], [64], [65]. Additionally, recent studies have demonstrated that the proteasomes from the brain have a different proteolytic profile than proteasomes from the spleen, consistent with proteasomes in the CNS having a unique structure or composition [66].

In spite of the obvious importance of understanding proteasome biology in the CNS, little is known about proteasome subunit expression in the various regions of the CNS. Immunohistochemical analysis, using antibodies that recognize the entire 20S proteasome complex, have demonstrated that the proteasome is ubiquitiously, although not homogeneously, expressed in the CNS [67]. Pyramidal cortical neurons and motor neurons in the ventral horn of the spinal cord demonstrated the most intense staining, with strong immunoreactivity evident in the nucleus, cytosol, and neuritic processes. In contrast to these two CNS cell types, the remaining cell populations of the CNS presented predominantly nuclear proteasome immunoreactivity. Proteasome expression was present in both neuronal and glial populations throughout the CNS. It is important to point out that proteasome immunoreactivity was evident in synaptic terminals, consistent with previous reports [68], indicating that the proteasome may play a role in synaptic homeostasis. Northern blot analysis reveals a brain region-specific pattern of proteasome subunit expression in the brain (Fig. 1). The C2 proteasome subunit appears to be predominantly expressed within the cerebellum, as compared to other CNS regions, with multiple isoforms of LMP2 and PA28β evident throughout the CNS (Fig. 1).

In contrast to immunohistochemical analysis, proteasome activity in the CNS appears to be predominantly cytosolic, with nuclear proteasome activity accounting for 10–15% of total proteasome activity in the CNS (J.N. Keller, personal communication). All eukaryotic cells contain mitochondrial proteasome-like activity [69], [70], although the amount of this proteolytic activity in the CNS has not been elucidated. Mitochondrial proteasome-like activity can be mediated by either PIM1 or Lon proteases, which can function individually or as monomeric complexes [69], [70]. Northern blot analysis demonstrates that Lon is evident in multiple brain regions (Fig. 1), consistent with its potential role in maintaining CNS homeostasis. Because these proteases are structurally distinct from the 20S proteasome, it is likely that the mitochondrial proteasome-like proteases may have dramatically different substrate specificities and function than either cytosolic or nuclear proteasomes. Even though the amount of nuclear and mitochondria proteasome-like activity accounts for only a small percentage of the total of proteasome activity, each may be particularly important in maintaining cellular homeostasis. For example, histones and a number of transcription factors have been demonstrated to be proteasome substrates (Table 1), with controlled degradation of transcription factors and damaged histones playing critical roles in maintaining nuclear homeostasis. Previous studies have demonstrated that mitochondrial proteasome-like activity is essential for mitochondrial biogenesisis, mitochondrial respiration, and preventing the accumulation of mitochondrial DNA alterations [69], [70]. However, the role of mitochondrial proteasome-like activity in each of these processes in the CNS has not been elucidated.

Additional proteins can bind to the 20S proteasome, resulting in the formation of a larger proteasome complex. The best characterized of these protein cap-like structures are the 11S and 19S proteasome complexes [1], [2], [6], [7]. Both the 11S and 19S complexes are composed of multiple proteins, with each protein believed to aid in protein unfolding and protein recognition [1], [2], [6], [7]. Additional studies have also revealed that 11S and 19S complexes may also play a role in additional, presumably nonproteasome associated, cellular functions including nucleotide excision repair [1], [2], [6], [7], [71]. However, it is important to point out that 11S and 19S caps do not possess proteasomal proteolytic activity, and contribute to the regulation of 20S proteasome activity only via their direct and indirect effects on the 20S proteasome. While it was initially believed that 26S proteasome complexes contained only 19S caps, recently it has been identified that hybrid proteasome complexes can occur. These hybrid proteasomes can contain a mixture of 11S and 19S caps, resulting in the formation of a distinct proteasome complex [72]. Together, these studies highlight the importance of understanding the expression and function of 11S and 19S subunits in the CNS.

Recent studies have demonstrated that proteasome inhibition may occur in a wide array of neurodegenerative disorders, including ischemia-reperfusion injury [73], Alzheimer’s disease [74], [75], and Parkinson’s disease [76]. In each of these conditions, the ability of proteasomes to generate fluorogenic substrates from peptides specific for individual proteasome activities has been demonstrated. It is important to point out that while these peptides can be extremely useful as a determinant of proteasome activity, they may not fully account for functional impairments in proteasome activity. For example, the ability to cleave a chymotrypsin-like substrate may be only slightly inhibited in a particular tissue, even though the ability of the proteasome to degrade a specific protein may be severely inhibited. Alternatively, the ability of proteasomes to generate fluorogenic peptides may be unaffected in a given condition or disorder, even though proteasome composition has been altered to such a degree that the normal sequential mode of proteasomal degradation does not occur. In such a scenario, improperly degraded proteins may be allowed to deleteriously interact with other cellular proteins, resulting in compromised neuronal vulnerability. In future studies, it will therefore be important to monitor the rate of proteasomal degradation of particular substrates in neurodegenerative disorders and to determine if proteasome substrates are properly or completely degraded.

In addition to neurodegenerative disorders, proteasome activity has been demonstrated to be impaired during the aging of the CNS [77], [78]. These data are in agreement with previous studies that have demonstrated that proteasome inhibition occurs during normal aging in non-CNS systems [79], [80], [81]. Interestingly, some CNS regions, including the brain stem and cerebellum, show decreases in proteasome activity only in extremely aged rodents [77]. These data suggest the possible existence of proteasome complexes which are either extremely vulnerable, or resistant, to age-related alterations. Healthy centenarians, and rodents placed on a dietary restriction regiment, exhibit a marked amelioration of age-related increases in protein oxidation and proteasome alterations [82], [83], [84]. The beneficial effects of caloric restriction are rapidly reversed upon the initiation of ad libitum diet [9], supporting the existence of reversible processes that are directly responsible for inhibiting proteasome activity.

As with aging, data from previous studies have revealed that CNS region-specific proteasome inhibition may occur in a number of neurodegenerative conditions [73], [74], [75], [76]. This suggests that proteasome inhibition may not occur globally in neurodegenerative conditions, or as the result of a global phenomenon in those conditions. It will be important in the future to determine which cell types in the CNS undergo a loss of proteasome activity during normal aging, and in neurodegenerative disorders. Based on previous studies, we would expect that mitotic cells (glia) would have higher basal levels of proteasome activity than post-mitotic cells (neurons) [8], [9]. It is possible that the loss of proteasome activity, during normal aging and in neurodegenerative conditions, is mediated by a selective loss of proteasome activity from mitotic or post-mitotic cells. At present it is unclear if, in addition to cell specific proteasome inhibition, there may be subcellular specific inhibition of the proteasome. For example, nuclear proteasome activity may be selectively impaired in some neurodegenerative disorders, mediating a pathology distinct from what would be expected from a predominantly cytosolic form of proteasome inhibition.

In addition to studies providing direct demonstrations of functional proteasome impairment, it is important to point out that numerous immunohistochemical studies have provided the initial evidence for probable proteasome inhibition in Alzheimer’s disease, Parkinson’s disease, and Lewy Body disease [85], [86], [87], [88]. The localization of the proteasome at these neuropathological sites was proposed to represent a possible breakdown in proteasome activity. Similar results have recently been reported to occur in several in vitro and in vivo models of spinocerebellar ataxia and Huntington’s disease [89], [90]. Interestingly, each of these polyglutamine disorders are associated with protein aggregation and increased levels of ubiquitinated protein aggregates, similar to Alzheimer’s disease, Parkinson’s disease, and ischemia-reperfusion injury [91], [92]. It will therefore be important to determine if proteasome inhibition occurs in polyglutamine disorders. Additionally, it is likely that immunohistochemical studies may provide possible clues as to how proteasome inhibition occurs in the CNS. For example, the co-localization of heat shock proteins (HSPs) with the proteasome suggests a role for HSP in proteasome-mediated proteolysis [85], [86], [87], [88], while Western blot analysis demonstrating that proteasome inhibition is not associated with a loss of overall proteasome immunoreactivity [73], [74] suggests that some post-translational event, and not a loss of overall proteasome expression, may be responsible for mediating proteasome inhibition.

Substrates must enter between the α- and β-subunits of the 20S proteasome, and be inserted within the core of the 20S complex, in order to be degraded. At present, the intracellular pathways responsible for mediating targeting, unfolding, and insertion of proteasome substrates is poorly defined. However, it is important to point out that alterations in any of these processes may have profound effects on proteasome activity. In such a model, alterations to nonproteasomal proteins, including HSPs, could result in direct impairment of proteasome activity. As discussed below, the mandatory unfolding of substrates, dependence on the utilization of a narrow entrance for substrate insertion, and requirement for multiple protein-protein interactions, may play important roles in mediating proteasome-inhibition in neurodegenerative disorders.

Increasing evidence suggests that oxidative stress may be responsible for at least some forms of proteasome inhibition in the CNS. Recent studies have demonstrated that oxidative modification of the proteasome, or interaction of oxidized proteins with the proteasome complex, occurs during normal aging in the spinal cord and in experimental models of stroke [73], [78]. It is interesting to point out that there is a significant elevation of proteasome complex oxidation in the spinal cord of young rodents, as compared with other CNS regions [78]. These data suggest that under some circumstances the proteasome is required to function in the presence of fairly rigorous levels of oxidative stress, undergoing detectible levels of oxidative damage that presumably does not adversely affect proteasome activity. Alternatively, in at least one neurodegenerative disorder associated with oxidative stress, Alzheimer’s disease, there is no detectible increase in proteasome oxidation (J.N. Keller, personal communication), suggesting that oxidative damage to the proteasome does not always occur in the presence of oxidative stress.

Although the source of ROS responsible for inhibiting proteasome activity in the CNS has not been elucidated, recent in vitro studies have demonstrated a possible role for monoamine oxidase-mediated ROS generation [93]. Additionally, previous studies have indicated that nitric oxide, and related species, can significantly inhibit proteasome activity [94], [95]. Once produced, ROS can cause elevations in lipid peroxidation products. These lipid peroxidation products can adversely affect cellular homeostasis in the CNS by rapidly interacting with cellular proteins. Cells of the CNS must therefore rapidly remove proteins that have been modified by lipid peroxidation products in order to prevent their nonspecific aggregation and subsequent accumulation. Numerous studies have indicated that proteins or peptides modified by the lipid peroxidation product 4-hydroxynonenal (HNE) can potently inhibit proteasome activity [77], [96], [97]. The inability of a broad-spectrum antioxidant to prevent HNE-mediated proteasome inhibition in neural cells suggests that HNE-mediated proteasome inhibition does not require further ROS generation [77]. Rather, it is believed that high levels of protein cross-linking and the formation of protein aggregates may serve as a physical block to the entrance of proteasome substrates, thus inhibiting proteasome activity.

However, in contrast to high levels of ROS, it should be noted that exposure to mild oxidative injury has been demonstrated to stimulate proteasome activity [98], [99], presumably through the initiation of favorable conformation changes in the 20S proteasome complex. The ability of the proteasome to increase its activity in response to mild oxidative stress reinforces the notion that the proteasome may function as a secondary defense in the CNS, serving to degrade oxidized, aggregated, or damaged proteins as they occur during oxidative conditions. Such degradation would prevent nonspecific protein-protein interactions from occurring; presumably preventing the formation of potentially deleterious protein aggregates. These data highlight the potential role proteasome inhibition may play in cell survival, oxidative stress, and the accumulation of damaged proteins following oxidative injury. Additionally, these studies indicate that even mild proteasome inhibition may cause increased levels of protein oxidation, and possible exacerbation of even low levels of oxidative stress.

Increasing evidence suggests that HSP family members may play a role in proteasome-mediated proteolysis. The best characterized of the HSP family members is Hsp70, which has been demonstrated to be involved in a diverse array of cellular activities ranging from protein trafficking to protein degradation [100], [101]. However, it is important to point out that efficient Hsp70 function requires the activity of two individual co-chaperones, Hsp40 and BAG-1 [102], [103], [104]. HSPs and proteasomes have been demonstrated to co-localize in vitro and in vivo [89], [90], with previous studies indicating a requirement for HSP in latent proteasome activity in some in vitro proteasome assays [105], [106]. It is likely that HSP family members play an important role in the targeting of protein substrates to the proteasome for degradation, and assisting in the unfolding of proteins necessary for proteasome-mediated degradation. HSPs would also be expected to play a critical role in maintaining proteasome activity during oxidative stress, where aggregated proteins could possibly be generated to levels that are sufficient for directly inducing proteasome inhibition. Recent studies support such a model, whereby neural cells overexpressing Hsp40 demonstrate a remarkable preservation of proteasome activity following a variety of oxidative injuries [107]. Elevated levels of HSP occur during normal aging, and in a wide array of neurodegenerative disorders including Alzheimer’s disease, ischemia-reperfusion injury, and Parkinson’s disease [100], [101], [102], [103], [104]. Based on the numerous studies indicating a neuroprotective role for elevated HSP expression [100], [101], it is possible that the elevation of HSP serves as an attempt by the cells of the CNS to cope with the intracellular alterations that occur during conditions associated with oxidative stress. We propose that a particularly important function of elevated HSP expression is to preserve proteasome function, via HSP-mediated protein folding, HSP-mediated protein disaggregation, and HSP-mediated protein trafficking to the proteasome. Each of these aspects would be extremely important in preventing the accumulation of oxidized proteins, and preventing proteasome inhibition from occurring as the result of oxidized proteins forming nonspecific protein-protein interactions with the active sites of β-subunits, or at the sites where proteins are inserted within the proteasome.

Previous studies have identified several endogenous proteins that may also be involved in proteasome regulation. Of particular interest is the protein, proteasome inhibitor of 31 kDa (PI31) [108], [109]. Recent studies have demonstrated that PI31 contains a proline rich tail that can be inserted within the 20S proteasome complex, competing with 11S and 19S caps for 20S proteasome binding [108], [109]. Northern blot analysis reveals that PI31 is expressed throughout the brain (Fig. 1), consistent with PI31 playing a role in regulating CNS proteasome homeostasis. By preventing the binding of these cap-like proteins, and possibly inhibiting the insertion of substrates within the core of the proteasome complex, PI31 would be expected to effectively inhibit proteasome activity. Increasing the expression of PI31 may be important during conditions of severe oxidative stress, as a means of temporarily preventing the association of excessively oxidized proteins with the proteasome, and shunting the oxidized proteins to a predominantly lysosomal-mediated mode of proteolysis. The low pH, and reduced levels of protein-protein interactions, make the lysosomal-mediated degradation of highly oxidized proteins a more desirable means of proteolysis than the proteasome.

Numerous studies now clearly demonstrate that inhibition of the proteasome is sufficient to induce cell death in both neuronal and glial cells. These studies have demonstrated that proteasome inhibitors can induce several hallmarks of apoptosis, including caspase activation, cytochrome C release, elevated p53 expression, chromatin fragmentation, and DNA laddering [110], [111], [112], [113], [114], [115], [116], [117]. The ability of proteasome inhibition to induce such a wide variety of cell death events suggests that proteasome activity plays a critical role in multiple aspects of neuronal homeostasis. Recent studies have indicated that the proteasome is directly responsible for the degradation of some cell death factors (Table 1), with inhibition of the proteasome sufficient to increase their levels to a presumably cytotoxic level. Additionally, the proteasome is responsible for preventing the accumulation of proteins not directly related to cell death, but which can contribute to neuron death by conferring an increased half-life to the given protein. For example, impaired turnover of steroid receptors or IP3 receptors may allow for prolonged, and potentially deleterious signal transduction, in response to even minor stimuli. Proteasome inhibition has also been demonstrated to increase the accumulation of cytotoxic amyloid beta peptide [24], [25], Presenilin [22], [23], and Parkin [21], which may play a role in Alzheimer’s disease and Parkinson’s disease, respectively.

However, it is important to point out that proteasome inhibition does not appear to induce neuron death in all neuron populations or experimental paradigms [118], [119], [120], [121]. These data raise the possibility that proteasome inhibitor toxicity may be cell-type-specific. For example, the proteasome is responsible for some forms of NFκB activation, which can have pro-apoptotic or anti-apoptotic effects depending on cell type [122], [123], meaning that proteasome inhibition could have very different effects on cell survival based on the differential role of NFκB in these two cell populations. Alternatively, these data could indicate the inadequacy of some neuronal populations to utilize nonproteasomal proteolysis, in order to maintain neuronal homeostasis. In such a scenario, cells able to upregulate the levels of lysosomal protein degradation, and utilize lysosomal-mediated proteolysis effectively, would be expected to exhibit little toxicity in response to the application of proteasome inhibitors. As described previously, cell specific differences may also be due to alterations in HSP capacity, with neurons possessing higher levels of HSP capacity being more resistant to proteasome inhibitor toxicity. In applying the knowledge obtained from in vitro studies to studies in the mature CNS, it is important to keep in mind that the majority of in vitro studies are conducted in cultures established from embryonic tissue, or tissue from early postnatal brain. As such, one must take into account the possibility that embryonic tissue may have a different dependence on proteasome activity than established neurons within the mature and developed CNS.

In addition to directly mediating neurotoxicity, application of proteasome inhibitors increases neural vulnerability to subsequent injury. In particular, proteasome inhibitors increase vulnerability to oxidative injury [93]. Increased vulnerability may be related to elevated levels of poly-ADP-ribosylation [110], which can result in energy depletion and impaired DNA stability. Increased vulnerability may also be due to alterations in cell signaling that occur as the result of transcription factors, and related proteins, having an increased half-life as the result of proteasome inhibition. The ability of mild, nontoxic, proteasome inhibition to increase vulnerability to oxidative stressors may be particularly important in aging, Alzheimer’s disease, and Parkinson’s disease. In each of these conditions, proteasome inhibition would be expected to occur gradually, in a step-wise manner, and not directly induce cell death within the CNS. However, once a certain level of proteasome inhibition is achieved, proteasome inhibition could then serve as a trigger, and increase the toxicity of subsequent stressors.

As proteasome inhibition may play a contributing role to neurodegeneration, it is important to determine mechanisms which may ameliorate proteasome inhibition. Such studies will ultimately rely on a greater understanding of how proteins are targeted to the proteasome, and degraded by the proteasome, in the CNS. However, even now several intriguing possibilities exist. One obvious target for ameliorating proteasome inhibition would be identifying mechanisms for efficiently upregulating the levels of HSP within the CNS. Increasing HSP family members would be expected to help in preserving proteasome activity, possibly serving to delay age-related proteasome inhibition. Alternatively, pharmacological interventions designed to stimulate proteasome activity within the CNS may provide some therapeutic benefit. Such treatments could possibly be utilized to counteract the natural loss of proteasome activity that is observed to occur within the CNS during normal aging, thus preventing or delaying age-related elevations in protein oxidation. Recent studies have identified a number of pharmacological proteasome activators [124], [125], [126], that may ultimately provide the basis for such treatments in the future. Alternatively, it may be possible in the future to increase the expression of specific proteasome subunits. Recent studies have identified a novel protein in yeast that is responsible for the transcription of a number of proteasome subunits [127]. Although no mammalian homologue has yet been identified, these data raise the possibility of utilizing such a protein to elevate potentially beneficial levels of proteasome expression in the CNS of humans.

The importance of the proteasome to CNS biology and pathology is only now beginning to emerge. It is likely that studies on this intriguing enzyme will yield important information on how oxidative stress occurs in the CNS, how protein turnover is regulated in the CNS, and may ultimately lead to the designing of useful therapies aimed at eliminating oxidative stress toxicity in the CNS.

Section snippets

Acknowledgements

The authors thank F.F. Huang and E. Dimayuga for technical assistance, and J. Gee, C. Lauderback, and A.J. Bruce-Keller for helpful discussions. This work was supported by grants from the American Heart Association (National Affiliate) Scientist Development Grant, Huntington Disease Society of America (Donnellon Family Fund), and the American Health Assistance Foundation (J.N.K.).

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