The Role Of The Ubiquitin Proteasome System Biology Essay

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The ubiquitin proteasome system functions to degrade unwanted proteins and its impairment have been linked to Parkinson's disease. UPS impairment leads to the accumulation and aggregation of unwanted proteins as Lewy bodies and Lewy neurites, causing dopaminergic neuronal death in substantia nigra of the brain. Parkinson's disease can be either familial or sporadic, with the former involving genetic factors while the latter involve a combination of both genetic and environmental factors. Mutations in parkin, UCH-L1 (ubiquitin C-terminal hydrolase L1) and α-synuclein genes will cause UPS failure while mutations in genes such as PINK1 (PTEN-induced putative kinase 1), DJ-1 and LRRK2 (leucine-rich repeat kinase 2) will cause mitochondrial dysfunction leading to UPS failure as well. All these mutations ultimately result in Parkinson's disease. Similarly, environmental factors such as neurotoxins, which include MPTP (1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine) and rotenone, and substances that induce aging will lead to UPS failure and thus Parkinson's disease. Many studies were done to research the role of UPS in Parkinson's disease but even up till now, there is no concrete evidence in proving their association. Contradicting findings were found and the actual underlying mechanism of how UPS impairment can lead to Parkinson's disease is still not understood. Hence, current research needs to focus in resolving contradictions and to discover concrete evidence in proving the association of UPS failure with Parkinson's disease.

2 Introduction

Parkinson's disease is a common, progressive neurodegenerative disease discovered by James Parkinson in 1817 (Inamdar et al, 2007; Sun et al, 2007), lagging just behind Alzheimer's disease (Kay et al, 2007). The symptoms include resting tremors, muscle rigidity and bradykinesia (Robinson, 2008; Inamdar et al, 2007; Sun et al, 2007). It was later discovered that such symptoms were initiated by a gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the brain (Werner et al, 2008), with the presence of Lewy bodies and Lewy neurites in remaining neurons (Markesberg et al, 2009; Werner et al, 2008). Further studies supported the fact that the loss of dopaminergic neurons, and thus dopamine neuronal transmission, are closely associated to the display of symptoms (Werner et al, 2008).

About 90% cases of Parkinson's disease are sporadic but increasing studies have shown possible link of the disease to genetic factors, accounting for about 10% of total cases (Robinson, 2008). Usually, it is individuals age 60 years & above that succumb to sporadic Parkinson's disease while autosomal dominant/ recessive early-onset familial Parkinson's disease affect individuals of age 40 years and below (Sironi et al, 2008). There are cases of autosomal dominant late-onset Parkinson's disease as well (Robinson, 2008; Inamdar et al, 2007).

Generally, factors causing either familial or sporadic Parkinson's disease are believed to impair the ubiquitin proteasome system (UPS) which results in detrimental protein aggregation in the brain (Lindsten et al, 2002). Dopaminergic neurons were observed to be most vulnerable to such aggregation (Robinson, 2008; Inamdar et al, 2007; Cookson, 2004). The UPS rely on 26S proteasome to degrade target proteins/ substrates tagged by ubiquitin molecules and this regulatory process involves many enzymes (Ventii and Wilkinson, 2008). A mutation in any of the UPS enzymes (Shimura et al, 2001) or target proteins/ substrates (Lim and Tan, 2007; Ciechanover and Schwartz, 2004; Tanaka et al, 2004) will prevent UPS from functioning properly, leading to protein aggregation and ultimately Parkinson's disease. Deubiquitinating enzyme (DUB), a type of UPS enzyme, acts as a binding partner for 26S proteasome to allow the recycling of ubiquitin for UPS to undergo continued tagging of other target proteins (Das et al, 2006). There are many types of DUB and a mutation in any of them was observed to impair UPS too (Ventii and Wilkinson, 2008; Ciechanover and Schwartz, 2004).

In terms of familial Parkinson's disease, the widely accepted events leading to it include the inherited gene mutation in parkin (Sironi et al, 2008; Werner et al, 2008), UCH-L1 (ubiquitin C-terminal hydrolase L1) (Werner et al, 2008; Das et al, 2006) and α-synuclein (Das et al, 2006) that results in UPS failure. The theory of oxidative stress causing mitochondrial dysfunction was also proven to impair the ATP-dependent (adenosine triphosphate-dependent) UPS (Irvine et al, 2008; Inamdar et al, 2007; Sun et al, 2007), eventually leading to Parkinson's disease. For this theory, inherited gene mutation in PINK1 (PTEN-induced putative kinase 1) (Irvine et al, 2008; Robinson, 2008; Sun et al, 2007), DJ-1 (Werner et al, 2008), parkin (Robinson, 2008; Inamdar et al, 2007; Sun et al, 2007) or LRRK2 (leucine-rich repeat kinase 2) (Schlitter et al, 2006) can be involved.

In terms of sporadic Parkinson's disease, it was observed to be caused by a combination of genetic and environmental factors (Inamdar et al, 2007; Lim and Tan, 2007; Dawson and Dawson, 2003) resulting in UPS failure as well. The genetic factors are spontaneous mutation in genes such as parkin and α-synuclein. The environmental factors can be neurotoxins or substances that induce aging (Robinson, 2008; Lim and Tan, 2007; Sun et al, 2007).

All in all, the role of UPS in Parkinson's disease has been an interest to many researchers as increasing studies have shown close association between UPS itself and Parkinson's disease (Lim and Tan, 2007; Tanaka et al, 2004; Ciechanover and Brundin, 2003). Various experiments were done to prove that a certain genetic or environmental factor will result in UPS failure and eventually Parkinson's disease (Sironi et al, 2008; Werner et al, 2008; Greene et al, 2003). However, there are only contradicting findings without any concrete discovery to date. Further studies are needed so as to resolve the contradictions and to achieve knowledge of actual underlying mechanism for the role of UPS in Parkinson's disease (Werner et al, 2008).

3 Ubiquitin Proteasome System and Parkinson's Disease

The ubiquitin proteasome system (UPS) acts to remove unwanted proteins from the body by ubiquitination (Shimura et al, 2001). This process involves the tagging of target protein with ubiquitin molecules and sending a signal to 26S proteasome for degradation (Shimura et al, 2001). The 26S proteasome is made up of a 20S core particle and two 19S regulatory particles. A loss in either 20S or 19S particle was observed to reduce UPS activity (McNaught et al, 2002), thus leading to Parkinson's disease.

Figure 1. Top part of the image shows that impairment of the ubiquitin proteasome system will lead to protein aggregation in the form of Lewy bodies. Lower part of the image shows the ubiquitination process. Image taken from Lim and Tan, 2007.

Many studies indicated the link of UPS impairment with Parkinson's disease due to the formation of protein aggregates, causing dopaminergic neuronal death (Robinson, 2008; Inamdar et al, 2007; Reinstein and Ciechanover, 2006). UPS impairment caused a chronic imbalance of misfolded proteins generation and its degeneration, leading to toxic protein aggregation in the form of Lewy bodies and Lewy neurites, ultimately causing Parkinson's disease (Lindsten et al, 2002).

3.1 Ubiquitination

Ubiquitination are divided into two stages: marking target proteins with ubiquitin molecules and degradation of tagged proteins by 26S proteasome (Shimura et al, 2001). The ubiquitin proteasome system (UPS) consist three main types of enzymes, namely E1, E2 and E3. E1 is an ubiquitin-activating enzyme; E2 is an ubiquitin-conjugating enzyme while E3 is an ubiquitin ligase (Shimura et al, 2001).

In the first stage, ubiquitin is activated by E1 and this activation requires ATP (adenosine triphosphate) for energy. The activated ubiquitin will be carried over to E2, forming a complex. E3 will recognize the complex and catalyse the transfer of ubiquitin to the protein, of which an isopeptide bond is formed between them (Tanaka et al, 2004). The addition of ubiquitin to the protein is repeated many times to eventually form a polyubiquitin chain (Robinson, 2008; Lim and Tan, 2007; Ciechanover and Brundin, 2003).

In the second stage, the polyubiquinated protein will be degraded by 26S proteasome into smaller peptides (Lim and Tan, 2007; Reinstein and Ciechanover, 2006; Ciechanover and Brundin, 2003). The smaller peptides are further degraded into amino acids by proteases (Reinstein and Ciechanover, 2006; Ciechanover and Brundin, 2003) while deubiquitinating enzymes will regenerate free ubiquitin molecules from the tagged protein after its degradation (Das et al, 2006).

3.2 Mutations in Ubiquitin Proteasome System Enzymes or Target Proteins

The ubiquitin proteasome system (UPS) contains many enzymes including E1, E2, E3 and deubiquitinating enzymes to facilitate ubiquitination. Hence, a mutation in any of the enzymes (Shimura et al, 2001) will prevent UPS from removing target proteins, resulting in protein aggregation that leads to dopaminergic neuronal death and thus, Parkinson's disease (Greene et al, 2003). Similarly, a mutation in target proteins (Lim and Tan, 2007; Ciechanover and Schwartz, 2004; Tanaka et al, 2004) may prevent the UPS enzymes from recognising their structures, eventually leading to UPS failure and thus Parkinson's disease as the enzymes cannot facilitate the degradation of target proteins (Ciechanover and Schwartz, 2004; Ciechanover and Brundin, 2003).

3.3 Lewy Bodies and Lewy Neurites

Failure of ubiquitin proteasome system (UPS) result in the accumulation of protein aggregates in remaining dopaminergic neurons in the form of Lewy bodies and Lewy neurites as target proteins can no longer be degraded by UPS (Robinson, 2008; Inamdar et al, 2007; Sun et al, 2007). Lewy bodies and Lewy neurites is considered the most obvious signal showing that an individual suffers from Parkinson's disease (Markesbery et al, 2009). However, autosomal recessive early-onset Parkinson's disease has a lack of it (Shimura et al, 2001).

The presence of Lewy bodies and Lewy neurites were believed to be detrimental but there are opposing voices saying that they may actually play a protective role as the cell divert toxic proteins to form insoluble inclusions, thus preventing the toxic proteins from destroying brain tissues (Irvine et al, 2008; Lim and Tan, 2007; Ciechanover and Schwartz, 2004). Lewy bodies and Lewy neurites are made up of many proteins, with α-synuclein being the major component (Markesbery et al, 2009). Other proteins include ubiquitin, proteasome subunits and substrates of parkin such as CDCrel-1 (cell division control related-1), Pael-R (parkin-associated endothelial-like receptor), synphilin-1 (Sun et al, 2007) and the glycosylated form of α-synuclein known as aSp22 (Haywood and Staveley, 2004; Shimura et al, 2001).

4 Familial Parkinson's Disease

Familial Parkinson's disease is caused by genetic factors and may affect the ubiquitination proteasome system (UPS) directly or indirectly. Genes affecting UPS directly include parkin (Sironi et al, 2008; Werner et al, 2008), UCH-L1 (ubiquitin C-terminal hydrolase L1) (Werner et al, 2008; Das et al, 2006) and α-synuclein (Das et al, 2006) whereby a mutation in them will impair UPS since their products are target proteins of UPS. Such mutations result in a loss of function as target proteins can no longer be recognised by UPS enzymes and be degraded, leading to their accumulation and aggregation in the brain causing dopaminergic neuronal death (Ciechanover and Schwartz, 2004; Ciechanover and Brundin, 2003). Also, products of parkin, UCH-L1 and α-synuclein genes target substances that can form components of Lewy bodies for ubiquitination. Thus, the mutations will prevent their products from targeting several substances for ubiquitination, leading to the formation of Lewy bodies (Shimura et al, 2001). With it, there will be dopaminergic neuronal death and ultimately Parkinson's disease.

Genes affecting UPS indirectly include PINK1 (PTEN-induced putative kinase 1) (Irvine et al, 2008; Robinson, 2008; Sun et al, 2007), DJ-1 (Werner et al, 2008), parkin (Robinson, 2008; Inamdar et al, 2007; Sun et al, 2007) and LRRK2 (leucine-rich repeat kinase 2) (Schlitter et al, 2006) whereby a mutation in them will lead to oxidative stress and thus mitochondrial dysfunction, disrupting the production of ATP (adenosine triphosphate). Without ATP, UPS cannot function properly and thus, cannot degrade target proteins leading to their accumulation and aggregation (Irvine et al, 2008; Inamdar et al, 2007; Sun et al, 2007). This ultimately causes Parkinson's disease as well.

4.1 Mutations in Parkin Gene

A mutation in parkin gene, the most common genetic factor causing Parkinson's disease, will lead to autosomal recessive early-onset Parkinson's disease (Sironi et al, 2008; Shimura et al, 2001). Parkin gene expresses parkin proteins which function as an ubiquitin ligase (E3) in the ubiquitin proteasome system (UPS) (Shimura et al, 2001). Thus, any mutation in parkin gene will impair the functioning of UPS.

Studies observed that parkin protein plays a role in recognising polyubiquinated proteins and helps in facilitating their degradation by binding with the subunit of 26S proteasome, Rpn10 (also known as S5a) (Sakata et al, 2003). A mutation in parkin gene cause the inability of such binding (Robinson, 2008; Lim and Tan, 2007) and the gene cannot produce proper parkin proteins that recognise structures of their target proteins. Hence, parkin proteins can no longer perform its ligase activity, causing UPS failure (Lim and Tan, 2007; Sun et al, 2007). This caused a detrimental accumulation of their target proteins or even parkin proteins itself that result in dopaminergic neuronal death and eventually Parkinson's disease (Robinson, 2008; Inamdar et al, 2007; Lim and Tan, 2007). It was also seen that parkin is neuroprotective as it can increase body's resistance against substances detrimental to neuronal survival (Sun et al, 2007; Cookson, 2004). Thus, a mutation in parkin gene will increase the vulnerability of neurons to toxins.

Parkin gene can undergo many different mutations to eventually cause autosomal recessive early-onset Parkinson's disease. These include point mutations, exon deletions and exon multiplications (Kay et al, 2007; Lincoln et al, 2003). The most common mutations occur in the RING-IBR (in between RING)-RING domain of parkin gene (Lucking et al, 2000). In a study done by Sironi et al on 150 human subjects, nine point mutations of parkin gene among other types of mutations were identified, two of which were novel. The study also saw that heterozygous mutation in parkin alleles is enough to cause Parkinson's disease (Sironi et al, 2008) as supported by studies done by other researchers (Clark et al, 2006; Schlitter et al, 2006; Oliveria et al, 2003). However, some other researchers rebutted this idea as they observed heterozygous parkin point mutations in individuals without Parkinson's disease too (Kay et al, 2007; Lincoln et al, 2003).

To prove that a mutation in parkin gene does cause Parkinson's disease, many studies were done on animal models as well. Experiments done on parkin knockout mice to impair UPS observed no degeneration of dopaminergic neurons (Palacino et al, 2004) though the mice displayed Parkinsonian-like symptoms (Palacino et al, 2004; Itier et al, 2003) and reduced dopamine transporters to uptake dopamine (Tanaka et al, 2004) which may explain the initiation of symptoms. The fact that dopaminergic neurons were not loss in such parkin knockout mice experiments where UPS is impaired is not in tune with the saying that parkin mutations will lead to dopaminergic neuronal loss and thus Parkinson's disease (Perez and Palmiter, 2005; Goldberg et al, 2003; Itier et al, 2003).

Experiments investigating parkin knockout drosophila however, did observe drosophila with dopaminergic neurons degeneration as their resulting effect together with the symptoms of Parkinson's disease (Cha et al, 2005; Whitworth et al, 2005; Greene et al, 2003). Therefore, the actual underlying mechanism of parkin mutations leading to UPS failure and thus Parkinson's disease is still not concrete enough. There is a demand for further research to justify this issue, especially on the cause of dopaminergic neuronal death.

4.2 Mutations in UCH-L1 (ubiquitin C-terminal hydrolase L1) Gene

UCH-L1 (ubiquitin C-terminal hydrolase L1) protein, the product of UCH-L1 gene, is a type of deubiquitinating enzyme in the ubiquitin proteasome system (UPS) (Nishikawa et al, 2003; Leroy et al, 1998) helping to recycle free ubiquitin molecules (Das et al, 2006). Thus, any mutation within UCH-L1 gene will impair UPS. Beside its hydrolase (deubiquitinating) activity, UCH-L1 can also perform ligase activity but this occurs only during its dimeric state (Das et al, 2006; Nishikawa et al, 2003). During its monomeric state, it can only perform hydrolase activity. UCH-L1 ligase activity acts to add ubiquitin to the already-formed polyubiquitin chain instead of catalysing the first addition of ubiquitin to target proteins (Ciechanover and Schwartz, 2004; Ciechanover and Brundin, 2003).

It was first discovered from a German family that a type of missense mutation in UCH-L1 gene, I93M (Das et al, 2006; Leroy et al, 1998), will lead to autosomal dominant Parkinson's disease (Das et al, 2006; Shimura et al, 2001) as found in two siblings in the German family (Leroy et al, 1998). Studies reported that I93M mutation resulted in decreased UCH-L1 hydrolase activity (Nishikawa et al, 2003; Leroy et al, 1998). With it, there will be less regeneration of ubiquitin molecules to allow continued process of ubiquitination on other target proteins. Hence, UPS will be impaired and target proteins will accumulate and aggregate to form Lewy bodies and Lewy neurites, causing dopaminergic neuronal death and ultimately Parkinson's disease (Lim and Tan, 2007; Sun et al, 2007; Reinstein and Ciechanover, 2006). An increase in ligase activity was observed in I93M mutation too (Ciechanover and Schwartz, 2004; Ciechanover and Brundin, 2003).

Interestingly, another type of mutation in UCH-L1 gene, S18Y, was observed to protect an individual against Parkinson's disease (Das et al, 2006; Healy et al, 2006; Nishikawa et al, 2003). The S18Y mutation greatly reduced the ligase activity of UCH-L1 while increasing its hydrolase activity (Nishikawa et al, 2003). However, it is still not known how these changes can protect an individual from Parkinson's disease. More research is needed to be done to better understand S18Y mutation. Nevertheless, it was seen that a decrease in hydrolase activity or an increase in ligase activity (abnormal UPS functioning) can result in Parkinson's disease as deduced from I93M and S18Y mutations.

To investigate whether hydrolase activity of UCH-L1 does play a role in causing Parkinson's disease, an experiment was done to inactivate UCH-L1 gene in mice, thus disallowing UPS from functioning properly (Das et al, 2006). The mice, however, did not display symptoms of Parkinson's disease but rather, Gracile Axonal Dystrophy syndrome as its resulting effect (Das et al, 2006). This contradicts the discussion earlier that a decrease in hydrolase activity in UCH-L1 will lead to Parkinson's disease, thus bringing back the question of whether a mutation in UCH-L1 gene will cause Parkinson's disease or not.

Some researchers questioned the link between UCH-L1 gene and Parkinson's disease as their research has found no association. One such study did proteasome analysis on substantia nigra of individuals suffering from Parkinson's disease and individuals that were healthy when alive (Werner et al, 2008). It was observed that the expression of UCH-L1 between brains of diseased and healthy individuals showed no significant difference, as supported by another study using proteasome analysis as well (Basso et al, 2004). Furthermore, the mutation found in the two German siblings was the only case of I93M mutation in UCH-L1 gene till now (Healy et al, 2006). With it, more extensive research involving animal models or human subjects are needed to better conclude the link between UCH-L1 gene mutations, and thus the role in UPS failure, with Parkinson's disease.

4.3 Mutations in α-synuclein Gene

The α-synuclein gene, which expresses α-synuclein protein, will lead to autosomal dominant Parkinson's disease when mutated (Shimura et al, 2001). Being the major component of Lewy bodies, the role of α-synuclein in causing Parkinson's disease is deemed significant (Markesbery et al, 2009). Though there is no concrete knowledge on the functions of α-synuclein, it was believed to play a role in the proper functioning of neurons (Inamdar et al, 2007; Cookson, 2004) and in regulating dopamine neurotransmission (Irvine et al, 2008; Inamdar et al, 2007).

Two main types of α-synuclein gene mutations were identified which include gene locus multiplications, and missense mutations namely A30P, A53T and E46K (Inamdar et al, 2007; Sun et al, 2007; Cookson, 2004). These mutations increase the susceptibility of α-synuclein proteins to aggregate as toxic fibrils or protofibrils and it is this forms of α-synuclein that integrate into Lewy bodies (Lee and Lee, 2002). Such aggregation will impair the ubiquitin proteasome system (UPS) by inhibiting its activity, resulting in the accumulation and aggregation of other proteins targeted by UPS (Lindersson et al, 2004).

Figure 2. Image A shows the presence of Lewy body, neuromelanin and macrophages on the substantia nigra in Parkinson's disease. Image B shows a Lewy neurite which was positive for α-synuclein. Image taken from Werner et al, 2008.

An experiment observed that aggregated α-synuclein will interact with the 19S particle of 26S proteasome, thus inhibiting its function to degrade target proteins of UPS (Synder et al, 2003). Hence, there will be an aggregation of such proteins leading to dopaminergic neuronal death and ultimately Parkinson's disease.

To further prove that a mutation in α-synuclein gene will cause Parkinson's disease, studies were done on animal models (Irvine et al, 2008; Sun et al, 2007; Cookson, 2004). Over-expression of α-synuclein was observed to cause UPS inhibition, thus decreasing its ability to remove unwanted proteins (Sun et al, 2005; Tanaka et al, 2001). Additional studies investigating over-expression of normal and mutant α-synuclein in mice and drosophila also observed the resultant effects as dopaminergic neuronal death, Parkinson's disease symptoms and formation of inclusions that include α-synuclein (Irvine et al, 2008; Dawson and Dawson, 2003).

However, other studies could not prove that α-synuclein gene mutations will result in Parkinson's disease symptoms and dopaminergic neuronal death (Sun et al, 2007; Cookson, 2004; Dawson and Dawson, 2003). In addition, it is still not clear whether ubiquitination does facilitate the degradation of α-synuclein and whether impaired UPS will really lead to the development of Parkinson's disease (Ciechanover and Schwartz, 2004; Ciechanover and Brundin, 2003). Thus, a lot more research is needed to be done in order to affirm the link between α-synuclein gene mutations and Parkinson's disease, especially on the involvement of UPS.

4.4 Mitochondrial Dysfunction

The theory of oxidative stress resulting in mitochondrial dysfunction, thus disrupting the production of ATP (adenosine triphosphate) was justified by many researchers to impair the ATP-dependent ubiquitin proteasome system (UPS) (Irvine et al, 2008; Robinson, 2008; Inamdar et al, 2007). As UPS requires ATP as its energy source during ubiquitination, failure to produce ATP will prevent UPS from functioning properly. Hence, UPS cannot degrade target proteins leading to their accumulation and aggregation. This causes dopaminergic neuronal death and ultimately, Parkinson's disease (Irvine et al, 2008; Robinson, 2008; Inamdar et al, 2007).

The genes involved in this theory include PINK1 (PTEN-induced putative kinase 1) (Irvine et al, 2008; Robinson, 2008; Sun et al, 2007), DJ-1 (Werner et al, 2008), parkin (Robinson, 2008; Inamdar et al, 2007; Sun et al, 2007) and LRRK2 (leucine-rich repeat kinase 2) (Schlitter et al, 2006) whereby a mutation in them will lead to mitochondrial dysfunction.

PINK1 gene mutations cause autosomal recessive early-onset Parkinson's disease (Reinstein and Ciechanover, 2006; Cookson, 2004). PINK1 protein, the product of PINK1 gene, is a mitochondrial kinase (Irvine et al, 2008; Robinson, 2008; Inamdar et al, 2007) that functions to increase the resistance of mitochondria against UPS inhibition and also plays a role in stress response (Inamdar et al, 2007). Thus, a mutation in PINK1 gene will remove its protection on mitochondria, increasing the risk of UPS inhibition and eventually result in a negative impact whereby there will be no production of ATP to ensure proper UPS functioning. This leads to the accumulation and aggregation of UPS target proteins and dopaminergic neuronal death (Park et al, 2006) causing Parkinson's disease. Likewise, PINK1 gene mutations will leads to mitochondrial dysfunction, thereby disrupting the production of ATP for UPS as PINK1 can no longer response to counteract oxidative stress (Irvine et al, 2008). It was also observed that PINK1 acts to regulate HtrA2, a type of mitochondrial enzyme, and a mutation in PINK1 gene will leads to decreased mitochondrial processing by HtrA2 (Robinson, 2008). However, the exact mechanism of how PINK1 can prevent mitochondrial dysfunction is still unclear (Inamdar et al, 2007).

Similarly, mutations in DJ-1 gene can cause autosomal recessive early-onset Parkinson's disease (Meulener et al, 2005). DJ-1 protein, the product of DJ-1 gene, is a homodimeric mitochondrial protein (Robinson, 2008; Inamdar et al, 2007; Cookson, 2004) acting as a chaperone and was observed to prevent α-synuclein aggregation (Irvine et al, 2008; Robinson, 2008; Cookson, 2004). DJ-1 protein is also believed to be an antioxidant that protects mitochondria against detrimental effects of oxidative stress (Moore et al, 2005). A mutation in DJ-1 gene will no longer prevent the aggregation of α-synuclein, thus allowing this consequence to impair UPS and ultimately leads to Parkinson's disease. DJ-1 gene mutations also lead to its product instability and will be degraded by UPS (Meulener et al, 2005; Moore et al, 2005), thus increasing the risk of mitochondria to be damaged by oxidative stress (Moore et al, 2005). This was supported by a study investigating the effects of DJ-1 knockout mice (Cookson, 2004). However, a study which did proteasome analysis on substantia nigra of diseased and healthy human subjects observed that the expression of DJ-1 between the two groups displayed no significant difference (Werner et al, 2008) as agreed by similar analysis done by Basso et al (Basso et al, 2004). This contradicts the initial thought that DJ-1 gene mutations will cause Parkinson's disease.

For parkin proteins, it was seen that it can interact with PINK1 proteins (Park et al, 2006) and DJ-1 proteins (Meulener et al, 2005; Moore et al, 2005) to regulate the structure and functions of mitochondria. With it, a mutation in parkin gene, which expresses parkin protein, can result in mitochondrial dysfunction (Park et al, 2006) as the proper structure and functions of mitochondria cannot be maintained. This leads to reduced ATP production, thus impairing UPS. This causes the accumulation and aggregation of its target proteins, leading to dopaminergic neuronal death and thus Parkinson's disease.

Different from PINK1 and DJ-1 gene mutations, a mutation in LRRK2 gene will lead to autosomal dominant early-onset Parkinson's disease (Inamdar et al, 2007). Although the exact function of LRRK2, which is a kinase (Irvine et al, 2008; Inamdar et al, 2007) is not known, it was believed to be a target protein for ubiquitination by parkin in the UPS (Smith et al, 2005). Over-expression of LRRK2 will lead to its aggregation (Smith et al, 2005) that may exceed the ability of UPS to remove it. Mutations in LRRK2 gene is also believed to cause mitochondrial dysfunction (Sun et al, 2007). However, the actual underlying mechanism of how LRRK2 mutations can cause the development of Parkinson's disease is still unclear (Irvine et al, 2008; Inamdar et al, 2007).

It was seen that for the theory of oxidative stress leading to mitochondrial dysfunction, a great deal of research is still needed to firmly conclude the relationship of mitochondrial dysfunction with Parkinson's disease. Mutations in PINK1, DJ-1, parkin or LRRK2 genes causing mitochondrial dysfunction, leading to UPS failure and dopaminergic neuronal death, thus eventually Parkinson's disease requires more concrete evidence to support their association (Cookson, 2004; Dawson and Dawson, 2003).

5 Sporadic Parkinson's Disease

Sporadic Parkinson's disease is the most frequently-occurred type of Parkinson's disease (Itier et al, 2003), accounting for about 90% of total cases (Robinson, 2008). It was observed to be caused by a combination of genetic and environmental factors (Inamdar et al, 2007; Lim and Tan, 2007; Dawson and Dawson, 2003) that can lead to mitochondrial dysfunction and UPS failure, causing dopaminergic neuronal death. The genetic factors are as mentioned earlier which include mutations in parkin, α-synuclein and DJ-1 genes. The only difference is that they are spontaneous mutation instead of being inherited. The environmental factors can be neurotoxins or any substances that induces aging (Robinson, 2008; Lim and Tan, 2007; Sun et al, 2007).

5.1 Neurotoxins

There are many neurotoxins that can induce ubiquitin proteasome system (UPS) failure and eventually leads to Parkinson's disease, usually with the involvement of mitochondrial dysfunction. MPTP (1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine) (Irvine et al, 2008; Robinson, 2008; Inamdar et al, 2007), pesticides (Lim and Tan, 2007; Sun et al, 2007), 6-OHDA (6-hydroxyl dopamine) (Inamdar et al, 2007; Lim and Tan, 2007; Sun et al, 2007) and heavy metals (Inamdar et al, 2007; Sun et al, 2007) are all neurotoxins acting as environmental factors that can cause sporadic Parkinson's disease.

5.1.1 MPTP (1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine)

MPTP is a mitochondrial complex I inhibitor which undergo oxidation to form MPP+ ion inside the body and is taken up by dopamine transporters, accumulating itself in the dopaminergic neurons (Fornai et al, 2005; Greenamyre et al, 2003). Such accumulation of MPP+ causes mitochondrial dysfunction and oxidative stress within dopaminergic neurons, leading to neuronal death (Irvine et al, 2008; Inamdar et al, 2007). UPS will be affected due to less ATP (adenine triphosphate) production by mitochondria and also, due to increased misfolded proteins generation caused by oxidative stress (Hoglinger et al, 2003). These prevent UPS from removing unwanted proteins efficiently and thus, lead to their aggregation causing dopaminergic neuronal death and eventually Parkinson's disease.

Studies involving animal models observed that MPTP resulted in the display of Parkinson's disease symptoms (Greenamyre et al, 2003), dopaminergic neuronal death (Fornai et al, 2005; Ved et al, 2005), formation of inclusions (Fornai et al, 2005) and inhibition of UPS (Fornai et al, 2005). Studies had also observed the relationship between MPTP and α-synuclein whereby α-synuclein is needed to allow MPTP to decrease UPS activity and cause dopaminergic neuronal death (Fornai et al, 2005). However, further research needs to be done in studying the formation of inclusion bodies due to the presence of MPTP as it is not known whether such inclusions do represent Lewy bodies and Lewy neurites (Fornai et al, 2005; Greenamyre et al, 2003). In addition, MPTP was seen to cause the inactivity and insolubility of parkin that threatens the neuroprotective role of parkin (Wang et al, 2005). This result in the aggregation of parkin (Wang et al, 2005) and impairment of UPS since parkin acts as an E3 in the UPS, leading to the development of Parkinson's disease.

5.1.2 Pesticides

There are three main types of pesticides, namely rotenone, paraquat and dieldrin which act as a neurotoxin, causing sporadic Parkinson's disease. Rotenone is a mitochondrial complex I inhibitor (Wang et al, 2006; Fornai et al, 2005) which enters the brain tissues causing mitochondrial dysfunction, thus inhibiting UPS due to reduced production of ATP from the mitochondria (Hoglinger et al, 2003). Effects of rotenone are very much alike those of MPTP which include the display of Parkinson's disease symptoms (Fornai et al, 2005; Greenamyre et al, 2003), dopaminergic neuronal death (Greenamyre et al, 2003), formation of inclusions (Fornai et al, 2005; Greenamyre et al, 2003; Hoglinger et al, 2003) and inhibition of UPS (Wang et al, 2006; Fornai et al, 2005; Wang et al, 2005). A study observed that dopaminergic neurons of substantia nigra are particularly susceptible to mitochondrial complex I inhibition despite the fact that rotenone induced the same level of mitochondrial inhibition throughout the whole brain (Greenamyre et al, 2003). It was also seen from a study that together with an over-expression of α-synuclein, rotenone can greatly degenerate dopaminergic neurons (Ved et al, 2005). Rotenone, too, can cause the inactivity and insolubility of parkin that threatens the neuroprotective role of parkin (Wang et al, 2005) and its ligase activity, thus impairing UPS.

Paraquat, whose structure has close resemblance to that of MPTP, is another pesticide acting as a neurotoxin that can cause sporadic Parkinson's disease (McCormack et al, 2002; Brooks et al, 1999). Effects of paraquat include Parkinsonian-like syndromes, oxidative stress, dopaminergic neuronal death (McCormack et al, 2002; Brooks et al, 1999), UPS inhibition (Wang et al, 2005) and α-synuclein aggregation (Manning-Bog et al, 2002; McCormack et al, 2002). Oxidative stress was observed to cause dopaminergic neuronal death (McCormack et al, 2002; Brooks et al, 1999), thus resulting in symptoms similar to that of Parkinson's disease. In addition, a study exposing mice to paraquat observed an increased level of α-synuclein aggregating in the brain (Manning-Bog et al, 2002). Such aggregation of α-synuclein will impair UPS as discussed earlier, eventually causing Parkinson's disease. Paraquat also caused inactivity and insolubility of parkin that threatens the neuroprotective role of parkin (Wang et al, 2005) and its ligase activity, thus impairing UPS. However, the underlying mechanism of paraquat causing neuronal death requires more research and concrete evidence as there are inconsistent findings from various studies (McCormack et al, 2002).

Dieldrin, also a pesticide, was believed to cause dopaminergic neuronal death, oxidative stress which resulted in mitochondrial dysfunction, UPS inhibition and α-synuclein aggregation (Sun et al, 2007). Research showed the significance of dieldrin in causing sporadic Parkinson's disease as studies comparing dieldrin levels in healthy and Parkinson's disease brains displayed a huge difference, with a higher levels in the diseased brains (Sun et al, 2007). Currently, the exact mechanism of dieldrin in causing sporadic Parkinson's disease is still unclear. Hence, further research has to be done to affirm this relationship.

5.1.3 6-OHDA (6-hydroxyl dopamine)

6-OHDA is a neurotoxin, with structure somehow resembling dopamine (Sun et al, 2007), which will induce oxidative stress (Vercammen et al, 2006; Wang et al, 2005) causing the impairment of UPS. Studies observed that initial exposure of 6-OHDA will increase the activity of UPS (Hoglinger et al, 2003) so as to remove misfolded proteins resulted from oxidative stress. It was only when the oxidative stress intensified that will cause UPS impairment (Hoglinger et al, 2003) as UPS cannot remove such unwanted proteins fast enough (Vercammen et al, 2006), leading to their accumulation and aggregation. This will then results in dopaminergic neuronal loss (Vercammen et al, 2006; Hoglinger et al, 2003) and ultimately Parkinson's disease.

Likewise, parkin protects dopaminergic neurons against toxins and this protective role is jeopardised by 6-OHDA, causing its inactivity and insolubility (Vercammen et al, 2006; Wang et al, 2005). With it, the ligase activity of parkin will be loss and there will be an aggregation of parkin (Wang et al, 2005), leading to UPS failure and dopaminergic neuronal death. However, a study did not observe dopaminergic neuronal death when mice were treated with 6-OHDA (Perez et al, 2005). Hence, there should be more studies on 6-OHDA to acquire its actual mechanisms in causing neuronal death and Parkinson's disease. The role played by UPS in developing Parkinson's disease due to 6-OHDA exposure needs more concrete evidence too.

5.1.4 Heavy Metals

Heavy metals such as iron, manganese and copper were believed to play a role in causing sporadic Parkinson's disease, with iron being the most common (Inamdar et al, 2007; Sun et al, 2007). Generally, heavy metals were observed to cause α-synuclein aggregation (Sun et al, 2007), leading to UPS impairment and eventually Parkinson's disease. In particular, iron results in oxidative stress leading to UPS impairment besides its ability to cause α-synuclein aggregation (Sun et al, 2007). Iron was seen to cause dopaminergic neuronal death too. Research studying the presence of iron in substantia nigra observed a higher level of iron in Parkinson's disease brains as compared to healthy brains (Inamdar et al, 2007). However, it is still unclear whether an increase in iron is the actual cause of dopaminergic neuronal death or whether it is just a by-product of dying dopaminergic neurons. Additional research is needed to justify its underlying mechanism. Interestingly, iron also caused the inactivity and insolubility of parkin that threatens the neuroprotective role of parkin, leading to parkin aggregation (Wang et al, 2005) and thus impairing UPS.

Another type of heavy metal, manganese, was observed to cause Parkinsonian-like symptoms and dopaminergic neuronal death besides α-synuclein aggregation (Sun et al, 2007). Studies observed that manganese is dependent on α-synuclein in inducing its toxic effects on cells (Sun et al, 2007). Similarly, manganese can jeopardise the neuroprotective role of parkin by altering its activity and solubility (Wang et al, 2005). To date, there is still not much extensive research on manganese in causing Parkinson's disease. Thus, more work can be done in this area to affirm the link by finding more concrete evidence.

5.2 Aging

Aging is another factor that can result in sporadic Parkinson's disease (Lim and Tan, 2007; Ciechanover and Brundin, 2003). It is a natural process but in the environment, there are substances that can speed up aging. Aging was seen to decrease the ability of ubiquitin proteasome system (UPS) in removing unwanted proteins (Zeng et al, 2005), thus causing their accumulation and aggregation. Aging too reduce body's resistance against oxidative stress, resulting in a higher level of misfolded proteins generation that exceed UPS's ability to remove them (Robinson, 2008; Sun et al, 2007; Ciechanover and Brundin, 2003). All these leads to dopaminergic neuronal death, especially aged neurons as they are more vulnerable to such aggregation (Robinson, 2008), and eventually Parkinson's disease.

One particular study using young and old animal models observed that the activities of UPS in older animal models were much lower than that of their younger counterparts, especially in the substantia nigra (Zeng et al, 2005). This further proves that aging will decrease the ability of UPS in removing unwanted proteins, leading to dopaminergic neuronal death. Additionally, aging was seen to cause insolubility of parkin (Wang et al, 2005; Pawlyk et al, 2003), thus removing the neuroprotective role of parkin. This will lead to UPS impairment, dopaminergic neuronal death and ultimately Parkinson's disease as discussed earlier.

6 Conclusion

In conclusion, the ubiquitin proteasome system (UPS) plays a significant role in Parkinson's disease as UPS impairment was seen to always cause nigral dopaminergic neuronal death and eventually, Parkinson's disease. However, studies on the genetic or environmental factors gave contradicting findings and there is not much knowledge on the actual underlying mechanisms in causing Parkinson's disease, especially in the involvement of UPS. Hence, current research needs to provide concrete evidence in resolving such contradictions and to understand the exact mechanisms of the causes of Parkinson's disease.

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