Free Essays - Biology Essays
Discussion of the ubiquitin-proteasome system in relation to the neuro-degenerative diseases, especially Parkinson's disease.
The ubiquitin-proteasome system isan incompletely understood and extremely complex intracellular pathway which isprimarily concerned with the degradation of cellular proteins - usually priorto recycling and reconstruction of the protein sub-units.
In the last two decades of the lastcentury, the elements of the system were unravelled and, as a result, we now understanda great deal more about the way that proteins are managed within the cell. Byunderstanding this system, we also now appreciate that it's malfunctioning hasa role to play in a number of disease processes, including a number ofmalignancies, Cystic Fibrosis, some muscle wasting syndromes, and severalneuro-degenerative diseases.
Ubiquitin pathways
It has been known that intra- andextra-cellular proteins turn over in the body at varying rates ranging from afew minutes to perhaps several weeks, for some time. Our initial understandingof this field revolved around the fact that when the lysosome was discovered byC. de Duve, it was thought to be the responsible organelle. It is now knownthat the lysosome is involved in the degradation of the extracellular proteinsand the discovery of the ubiquitin pathway opened up our understanding of thedegradation and circulation of the intracellular proteins.
The pathway is highly complex andvery carefully regulated.
In broad terns, the ubiquitin-proteasomesystem involves two basic processes. Firstly it involves the conjugation ofmany ubiquitin molecules to the substrate and then, secondly, it involves thebreakdown of the tagged protein by the proteasome complex. Although research isprogressing at a huge rate our understanding of the system is still far fromcomplete.
Proteolysis
Proteolysis is a dynamic processwithin the cells of an organism. Proteins are constantly being degraded intotheir constituent amino acid sub-units and then reassembled into new proteincompounds. The degradation is carried out by the proteases. This is a processwhich liberates the energy of the peptide bonds.
In the context of this piece, thereis a fundamental division between the proteolysis that occurs (from aphysiological point of view) outside of the body, in the lumen of the gut inthe normal process of digestion, and the completely intracellular proteolysisthat occurs in the restructuring and metabolic processes within the cell.
It is also important to make thedistinction in the second group, between the totally intracellular proteins,such as actin and myosin, and the (topologically) extra-cellular proteins suchas the blood coagulation cascade proteins. This latter group remaintopologically extra-cellular, and enter within the confines of the cell througha pinocytotic mechanism to be eventually exposed to the proteolytic enzymes ofthe lysosome, where they are eventually degraded.
Regulation of the ubiquitin-proteasome system
This is an immensely complex systemand it is not appropriate to go into significant detail in this piece, but afew words of explanation are in order. In broad terms, the process can eitherbe regulated at the level of the ubiquitination process, or at the level of theproteasome activity. The pathway is regulated by very delicate and sensitivemechanisms at a myriad of points along its route, but some physiologicalprocesses are associated with a massive upheaval in the whole system.
Physiological examples of thiswould be when mammals fast or hibernate there is massive muscle degradation.Another example is in the case of insect metamorphosis (Muller et al.1995). Pathological examples occur in malignant cachexia and denervation(Lecker et al. 1999) (Mitch et al. 1996)
It is self-evident that, in such acomplex process, involving many steps and potentially a multitude of proteinswithin the cell, the potential for pathology is enormous. Perhaps we should besurprised that the system appears to work as spectacularly efficiently as itdoes most of the time. Having said that, it is now appropriate to consider thepotential for disease in the human.
Disease processes that stem from the ubiquitination process
As we have observed above, the potentialfor pathology in the human is enormous when this process malfunctions. Themalfunction can vary in severity from a major enzyme failure such as the E1enzyme, which is uniformly lethal, all the way down to mutations in otherenzymes that only marginally affect the overall process and are effectivelysub-clinical in their effect.
The spectrum for human diseaseprocesses in the malfunction of the ubiquitin-proteasome system is thereforeenormous. We can broadly categorise it into two distinct groups. Firstly thereis the group of conditions that stem from a downgrading of the system's abilityto degrade proteins arising either from a loss of function or mutation in theubiquitin-proteasome system, or a mutation in the target substrate which effectivelyresults in a stabilisation in the target protein and secondly, there are thegroup that arise from processes that increase the degradation of targetproteins. In the research field, manipulation of these mechanisms are extremelyuseful in giving us glimpses into the complexity of the wholeubiquitin-proteasome system. (Glickman 2002)
In this piece we are primarilyconcerned with the neuro-degenerative diseases but when theubiquitin-proteasome system malfunctions, as we have pointed out earlier, thereare a myriad of potential pathologies that are possible. In passing, we couldusefully look at some of the mechanisms that underlie the pathology of somemalignancies since, an understanding of their aetiology has direct implicationsfor the understanding of the neuro-degenerative disease mechanisms. (See onunder drug development)
Manymalignancies have been found to fundamentally arise from one of two processes -either from the stabilisation (and therefore failure of degradation) ofoncoproteins or the destabilisation (and therefore increased degradation) oftumour suppressant genes. One of the major triggers to the onset of thesepathological states has been shown to be a virus. To take a specific example,in the case of human cervical cancers, the infecting human papillovirus (HPV)is categorised into high risk (eg. E6-16 or E6-18) and low risk classes(eg.E6-11). In vitro studies have shown that the difference in mode of actionbetween these virus groups is their ability to allow targeting of the p53protein. The most aggressive forms of cervical cancers have the lowest levelsof p53. The implication is that the high risk viruses specifically target theexpression of the p53 protein rendering it destabilised and therefore more proneto ubiquitin-proteasome system degradation.
Similarpatterns of activity by removal of the supressor to the oncoprotein(cyclin-dependent kinase inhibitor p27 Kip1) by a mechanism of increasedubiquitin mediated degradation, have been demonstrated in prostate, breast andcolorectal cancers - although viral aetiology has not yet been implicated inany of these forms. It has been suggested that a similar type of mechanism canaccount for the apparent differing degrees of apparent aggression in some of theneuro-degenerative diseases. (Loda et al. 1997)
There appears to be a strongcorrelation of the p27 protein levels and the aggressiveness of these variouscarcinomas and this appears to be because it plays a regulatory role in theprogression of the cell from the G1 stage to the S stage in mitosis. (Sherr& Roberts 1999). By reducing the level of p27, there appears to be anexplosive proliferation in the mitotic activity in the cell associated with theclinical manifestation of malignancy. (Slingerland & Pagano 2000) (Talishaset al. 1999)
In this piece we are concernedprimarily about the neuro-degenerative diseases. Our current knowledge islimited, but expanding at a rapid rate. We believe that theubiquitin-proteasome system plays a fundamental role in the development of theembryological human brain. Some neuro-degenerative diseases have been studiedin detail. It is worth considering Angleman Syndrome as a precursor to theother major diseases that we shall also consider later, as the pathway ofpathology is better understood than most. We believe that the syndrome arisesas a result of a specific mutation in the gene which codes for E3 ligase(Kishino et al. 1997). E6-AP has been specifically implicated in the causationof Angleman Syndrome which is typically characterised by mental retardation,seizures, abnormal gait and inappropriate laughter (Laan et al. 1999). Theactual protein which has been denatured or stabilised has not yet beenidentified. We do know, however, that it is independent from E6. It couldpossibly be one of the substrates of E6-AP. As we have discussed earlier weknow that the HPV virus (responsible for cervical carcinoma) targets the p53protein in an E6-dependent mode. Mouse studies show that E6-AP is stronglyimplicated in the aetiology of Anglemann's syndrome. The defective gene islocalised to 15q11-q13. Experimental and post-mortem studies show abnormalitiesin the Purkinje cells and the hippocampal neurones in every case (Albrecht etal. 1997).
The accumulation of ubiquitinconjugates and / or inclusion bodies have been found in a broad spectrum ofneuro-degenerative diseases. Some will produce characteristic appearances underthe electron microscope. The Lewy bodies in the brain stem being the hallmarkof Parkinson's disease, the neurofibrillary tangles of Alzheimer's disease,nuclear inclusions in the polyglutamine extension disorders such asHuntingdon's Chorea and Kennedy's syndrome together with spinocerebellarataxia. Bunina bodies are described in Amyotrophic lateral sclerosis
In all these cases, theubiquitin-proteasome system is strongly suspected but not yet definitelyimplicated. One of the reasons for this is the fact that both Alzheimer'sdisease and Parkinson's disease are not well defined, discrete clinicalentities, but clinical syndromes with different aetiologies. Parkinson'sdisease is the most common of all of the neuro-degenerative movement diseases.It is characterised, on a micro-anatomical level, by a progressive and extensiveloss of the dopaminergic neurones in the substantia nigra pars compacta.(Eriksen et al. 2005)
It could be that the discovery ofthe Lewy inclusion bodies or the neurofibrillary tangles, which are known to bethe physical manifestation of ubiquitin-proteasome system conjugates, mayactually be only secondary to the basic pathology and reflect the unsuccessfulattempts by the ubiquitin-proteasome system to eliminate damaged, modified orabnormal proteins.
The initial hypothesis describedthese accumulations as the natural tendency of abnormal proteins to accumulateand aggregate (Johnston et al. 2000) but more recent work suggests that thismay be a naive view and the whole process may be far more complex involving anumber of different intra-cellular mechanisms (Fabunmi et al. 2000) - one ofwhich may be the actual inhibition of the ubiquitin-proteasome system by theaccumulated proteins themselves (Bence et al. 2001).
Whatever the actual mechanism, itwould appear that the aggregation or clumping of these abnormal proteins is acommon factor in many of the hereditary neuro-degenerative diseasesparticularly the sporadic varieties.
In Parkinson's disease thesituation appears to be particularly complex as far as the ubiquitin-proteasomesystem is concerned. Mutations in A53T (alpha-synuclein) have been positivelyidentified as being implicated in the autosomal dominant forms of Parkinson'sdisease. Further work then discovered the same abnormal protein in the Lewybodies in sporadic Parkinson's disease and some forms of dementia includingAlzheimer's Disease, particularly those forms of Alzheimer's Disease which arecaused by genetic abnormalities (Kruger et al. 2000)
The alpha-synuclein protein istargeted by the proteasome (Bennett et al.1999) but we do not yet know if it isthe mutations that affect its stability and therefore lead to its eventualaccumulation and subsequent disruption of the cellular function. This is avital point that we shall return to later. Although we can demonstrate that theLewy bodies contain alpha-synuclein and varying amounts of ubiquitin, theexperimental evidence does not show whether it is conjugated synuclein thatforms the major part of the accumulated material.
There is new evidence thatexperimental accelerated formation of inclusion bodies by the mechanism ofproteasome inhibition, actually protects against dopaminergic cell death whichis actually contrary to previous experimental prediction (Setsuie et al 2005).This implies that the relationship between ubiquitin-proteasome system anddopaminergic cell death is clearly more complex than was originally thought.
There is a German family that hasbeen extensively investigated, who carry a variant mutation of the UCH-L1codinggene which manifests itself as Parkinson's disease (Leroy et al. 1998). Itwould appear that this mutation does not completely impair the function of theenzyme, but reduces its ability to function. From evidence gleaned from thestudy of this family it would appear that this mutation results in a reductionof the amount of free ubiquitin inside the cells and, as a result, there isless ubiquitin available to degrade other (as yet unidentified ) toxicproteins. It is worthy of note that a mutation in this same gene, UCH-L1, isresponsible for another neuro-degenerative disease called gracile axonaldystrophy in mice which has the clinical manifestation of sensory ataxiafollowed by motor ataxia as the disease progresses. (Saigoh et al. 1999)
Another important protein which isrelevant to the pathology of Parkinson's disease is known as Parkin, which is a465 amino acid residue protein which has certain structural and topographicalsimilarities to ubiquitin at the -NH end and a RING finger structure at the-COOH end. Mutations in the same gene appear to produce theAutosomal-recessive Juvenile Parkinson's variant which is the commonestfamilial form of Parkinson's disease (Kitada et al. 1998). This variant doesnot have the Lewy bodies which are the trade mark of the sporadic forms of thedisease.
Parkin has been identified as aubiquitin-protein ligase (Shimura et al 2000) which appears to act inconjunction with enzymes UBCH7 and UBCH8. Investigations have shown that themutant Parkin from patients with Autosomal-recessive Juvenile Parkinson'svariant have lost the ubiquitin ligase activity (Zhang et al. 2000). In itsnormal form, Parkin is believed to ubiquinate (and therefore promote thedegradation) of several proteins, one of which is CDCrel-1 (a septin GTP-ase)which acts in the pathway involved in the inhibition of exocytosis by virtue ofits actions on syntaxin (Zhang 2000). The discovery of this action of Parkin isof great importance as it points clearly to a direct implication of this enzymein a fundamental role in the pathogenisis of Parkinson's disease. In fairness,it is not yet possible to say which of the possible substrates of Parkin areactually implicated (or how), but there is a lot of current research on thesubject.
The relevance of theubiquitin-proteasome system in the pathogenesis of neuro-degenerative diseasesis thereby demonstrated by the consideration of these three distinct, butrelated, clinical forms of Parkinson's disease and these three proteins(Parkin, alpha-synuclein and UCH-L1) all experimentally proven to be linked tothe pathological process even though we cannot yet, with certainty, pin pointthe exact pathways involved.
In Alzheimer's Disease there isalso found an accumulation of ubiquitin with Tau in the characteristic form ofboth neurofibrillary bundles and senile plaques. It should be noted that Lewybodies also occur in some forms of the disease. Rather like Parkin inParkinson's disease, the role of the protein Tau in Alzheimer's Disease is notclearly defined. In exactly the same way that we passed comment on the role ofthe ubiquitin-proteasome system in neuro-degenerative diseases generally, it isnot possible to say whether the aberrant proteolysis is a primary cause or asecondary effect of some deeper pathology. As suggested earlier, it may be thatthe aberrantly folded proteins actively inhibit the ubiquitin-proteasome system(Bence et al. 2001)
More recent evidence has thrownfurther light on the issue suggesting a more direct link between theubiquitin-proteasome system and Alzheimer's Disease in the form of thediscovery of a frameshift mutation in the ubiquitin transcript resulting in anextra 20 amino acids moieties being added to the ubiquitin molecule. This hasbeen found in several variants of Alzheimer's Disease, most consistently in thelate-onset non-familial variant (Van Leeuwen et al. 1998). The functionaldifference in this extended form of ubiquitin was that the molecule wasfunctioned perfectly well in polyubiquitination, but the resulting polymerchains could not then be disassembled by the deubiquinating enzymes (Lam et al.2000). It therefore inhibited the degradation of the polyubiquinated substrateby the 26S proteasomes. It follows that this frameshift mutation in the brainleads to the inhibition of the ubiquitin-proteasome system with the subsequentaccumulation of neurotoxic proteins and characteristic patterns of clinicalexpression of the disease..
This mechanism has also beendiscovered in other neuro-degenerative disease states such as Down's syndrome(Van Leeuwen et al. 1998) and supra-nuclear palsy (Fergusson et al. 2000). Itis therefore not clear how the same pathological process appears in three (admittedlysimilar) neuro-degenerative diseases but produces three quite differentclinical syndromes.
Part of the suggested solution tothis situation are the presenilins (PS1 and 2) that appear to be involved inthe normal metabolic pathways involving amyloid proteins APP. (Steiner 1998). Anumber of forms of the early onset type of Alzheimer's Disease have implicatedaberrations in the PS genes, most frequently the PS1 gene. Both PS1 and PS2 arecontrolled by the ubiquitin-proteasome system (Kim et al.1997)
Again we have the problem ofascribing the role of cause or effect in this particular process. In just thesame way that we described with Parkinson's disease where differentubiquitin-proteasome system-related abnormalities are associated with differentclinical expressions of Parkinson's disease variants, there are differentubiquitin-proteasome system-related abnormalities which are seen in thedifferent forms of Alzheimer's Disease . We observe that that disturbance inthis pathway is an associated feature of Alzheimer's Disease, but furtherresearch is needed to decide it's exact role in the aetiology of the condition.
A similar type of process isimplicated in the pathogenisis of the Huntingdon's Chorea group ofneuro-degenerative diseases. It appears that there is an instability in thegenome that leads to another frameshift type of abnormality. This time itresults in an expanded 5'-CAG repeat segment which translates into apolyglutamine extension on the -NH terminal. In Huntingdon's Chorea the gene isknown as Huntingtin. The Huntingtin coded protein has not yet been isolated.
In a similar process in theconditions of the spinocerebellar ataxias (three clinical forms) there arethree abnormal proteins, one associated with each form - Ataxin 1-3, and again,in another similar process, the AR protein is abnormal in the condition ofspino-bulbar muscular atrophy. (Ross et al. 1999)
These polyglutamine extendedproteins accumulate in inclusion bodies inside the nucleus and are attached toubiquitin molecules (Lieberman and Fischbeck 2000).
Two proteins at least are degradedby the ubiquitin-proteasome system- Huntingtin (Kalchman 1996) and ataxin1(Cummings et al. 1999). In vitro tests on ataxin1suggest that it is theinability of the ubiquitin-proteasome system to remove the abnormally foldedprotein that leads to its accumulation.
One hypothesis holds that theinclusion bodies found in these neuro-degenerative diseases are a primitiveattempt on the part of the cell to store the proteins that cannot be removed bythe more normal means. If this is the case then the original hypothesis thatthe inclusion bodies were toxic aggregates is actually wrong as the inclusionbodies would therefore serve a protective purpose (Cummings et al. 1999).
Certainly there is some work(currently in its early stages) which appears to show that the various forms ofinclusion body in the various neuro-degenerative diseases, are a type ofscavenger mechanism designed to collect and store these abnormal proteins,and that attempts by the metabolic pathways to deal with them either byremoving E6-AP or by generating chaperone proteins, are actually the processesresponsible for the expression of the clinical manifestations of the diseaseprocess (Cummings et al. 1999).
The ubiquitin-proteasome systemalso plays a role in many of the conditions that result in muscle wasting. Wehave remarked on this process earlier in passing. Muscle wasting can be theresult of a number of physiological processes such as denervation andimmobilisation from any cause and also pathological processes such asmalignancies and starvation. Any of these processes can trigger or activate theubiquitin-proteasome system and cause induction of many of its associatedenzymes. The clinical manifestation of this is muscle wasting (Mitch &Goldberg 1996)
The N-end rule pathway is certainlyinvolved in the degradation of the muscle proteins although it is not yet clearjust how the muscle proteins come to be converted into appropriate substratesfor the pathway. There are clearly one (or many) signalling or inductionprocesses that initiate the process, but the more obvious candidates, such astumour necrosis factor, are not directly involved. Some sources have recentlydescribes the ubiquitin ligases as being involved (Bodine et al. 2001), but thesituation is far from clear as they do not appear to be involved in the N-endrule pathway.
Drug development
We have already hinted at therelevance of the ubiquitin-proteasome system in the possible field ofpharmacology. The thorough understanding of the metabolic pathways involvedclearly is essential to the process of trying to design drugs that will targetspecific steps or areas, with a view to mitigating or minimising the pathologicalprocesses that are occurring. Sadly, it is the very complexity and diversity ofthis process that makes it both tantalisingly attractive and unbelievablyfrustrating to target. It is by virtue of the fact that theubiquitin-proteasome system appears to be active in so many of the cellularregulatory pathways that modification of one area may very well have unwantedimplications in other, non-diseased, parts of the cell.
Enzyme inhibition, which is theclassic mode of drug action in such cases, may possibly confer advantage orbenefit in short term courses but the challenge is to find the appropriatemargin between therapy and toxicity.
Areas that have already beenexplored are of greater relevance to disease processes not directly covered bythis piece, but may well be found to have implications which are directlyrelevant. The malignancies have shown response to certain enzyme inhibitors(Golab et al.2000). In closer connection with the subject of neuro-degenerativediseases there has also been progress in treating brain infarcts (Phillips etal. 2000) and autoimmune encephalomyelitis (Vanderlugt et al. 2000)
In the case of autoimmuneencephalomyelitis the drugs act by preventing the activation of NF-B, therebypreventing the activation of an inflammatory response in the nerve tissues. Inaddition to the possibility of direct enzyme inhibition, an alternativeapproach can be to target particular E3 enzymes by phosphopeptides (Yaron etal.1998) This is not quite as straightforward as it may appear at first sightas inhibition of E3 may indeed produce benefits in terms of reducing excessiveactivity in some aspects of the immune processes, but it may also act bystabilising catenin, so that it can produce the obviously unwanted effect ofcausing malignant change in otherwise benign cells.
Discussion and conclusions
In this discussion we have seenthat the ubiquitin-proteasome system pervades every part of the cell andregulates the proteins in the cytoplasm, organelles and the nucleus. Even theprotein regulating and transcribing system of mRNA itself is ultimately underthe scrutiny of the ubiquitin-proteasome system (Laroia et al. 1999). Althoughwe have not discussed it in this piece, except in passing, it is the peptideproducts of the proteasome that ultimately decide the fate of the cell bytriggering the immune response if it is recognised as a tumour or infected andtherefore destroyed, or spared if it is recognised as self.
We still do not understand all ofthe processes of ubiquitinisation but or understanding is increasing rapidly.Perhaps one of the most important by-products of this new-found understandingis the fact that with each new step of the pathway found comes the possibilityof drug discoveries that will regulate that particular step and open up a newfield in the search for new therapeutic advances in the areas ofneuro-degenerative disease and cancer therapy.
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