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Parkinson’s Disease is the second most common neurodegenerative disease, after Alzheimer’s. Onset typically occurs late in life, affecting approximately 1% of 65 year olds, with the prevalence increasing to 4-5% by age 85 (Dawson & Dawson 2003). There are also rare cases of early-onset Parkinson’s, which are usually familial. Research into the gene mutations discovered in such hereditary cases has also contributed to the understanding of the aetiology of the spontaneous, late onset form of the disease.
Parkinson’s Disease (PD) is characterized clinically by tremors at rest, bradykinesia (slowness of voluntary movement), muscle rigidity, decrease in postural reflex and facial expression and an altered gait (Kumar et al. 2005). A subset of patients (10-15%) also develop dementia. Symptoms are progressive and result in decreased mobility and eventually severe disability.
The symptomatic motor disturbances arise from the progressive loss of dopaminergic neurons in the substantia nigra of the brain. This results in a decrease in the dopaminergic content of the striatum. These areas play an important role in modulating feedback from the thalamus to the motor cortex.
This report aims to investigate the current knowledge of the aetiology of PD, by examining evidence in the literature. It is crucial to understand the pathological mechanisms underlying the selective destruction of dopaminergic neurons in PD so that effective treatments and prophylaxis can be developed.
Researchers have studied the molecular mechanisms of PD pathogenesis using a number of techniques: in vitro tissue cultures of human and animal neurons, post-mortem human brain tissue, mouse models of the disease, genetic studies and more novel techniques such as the use of ‘cybrids’. Evidence from all of these will be amalgamated and conclusions drawn.
That PD is generally associated with old age must be considered an important clue when trying to elucidate the causal mechanism of PD. The same is also true of the most common neurodegenerative disease, Alzheimer’s Disease (AD). Both are also characterised by an accumulation of protein aggregates resulting in progressive neuronal loss, suggesting a common underlying pathology.
Histological brain sections of PD patients shows characteristic, large inclusion bodies in the cytosol of surviving neurons of the substantia nigra, as well as locus ceruleus and surrounding brainstem nuclei, called Lewy bodies (Kumar et al. 2005). These are aggregates of ï¡-synuclein (Spillantini et al. 1997), a protein whose gene (SYN, aka PARK 1) has been linked to familial PD (Athanassiadou et al. 1999), as well as other proteins such as ubiquitin and synphilin-1. It is unclear whether these aggregates contribute to the pathogenesis, are a simple by-product or even part of an attempted protective mechanism, described as the aggresome theory (McNaught et al. 2002). Some evidence has recently been produced by Setsuie and colleagues (2005), using a PD rat model in which proteasome inhibitors caused inclusion formation, which resulted in decreased dopaminergic neuronal death that normally follows 6-hydroxyl dopamine (6-OHDA) administration.
Lewy bodies are also found in low numbers in normal aging and AD (Jellinger 2001). However, Lewy bodies are not found in some cases of juvenile onset PD, which suggests that the inclusions are not crucial for neuronal death in the substantia nigra (Fahn & Salzer 2004). Animal models of the disease, created using neurotoxins such as rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or transgenic mice that overexpress human SYN gene (for ï¡-synuclein) mutations, do not faithfully replicate the structure and antigenicity of the Lewy bodies found in PD (Dickson 2001). This highlights the problems associated with designing and producing an accurate animal model of human disease, which can be valuable tools, despite some limitations.
Although the precise role of Lewy bodies in the pathogenesis of PD is still unclear, the accumulation and aggregation of proteins suggests that there is a deficit in the cellular systems that normally remove and degrade abnormal proteins. The ubiquitin-proteasome system (UPS) is one such pathway, and there is growing evidence that implicates this system in PD.
In conjunction with the enzymes E1, E2 and E3, ubiquitin is activated and attaches to abnormal proteins to form a polyubiquitin chain. The proteasome recognises this complex and degrades the unwanted protein. The ubiquitin polymer is released from the targeted protein and digested by ubiquitin carboxy-terminal hydroxylases (UCHs), to release ubiquitin monomers back into the system (Alberts et al. 2002). Ubiquitination and recognition of proteins to be degraded are ATP-dependent processes. If the activity of this clearance pathway decreases, misfolded or oxidatively damaged proteins will accumulate rather than being recycled (Sherman & Goldberg 2001).
Studies of the rarer, familial cases of PD have revealed evidence that this system is involved in PD aetiology, which has aided the understanding of the pathogenesis of sporadic PD. Gene mutations for two proteins that are involved in the UPS are of particular significance. Kitada and colleagues (1998) demonstrated a link between mutations in the parkin gene (aka PARK 2) and familial incidence of autosomal recessive juvenile parkinsonism (AR-JP) in Japanese families. Parkin is an E3 ligase within the UPS, and has been shown to have a neuroprotective role (Petrucelli et al. 2002). Despite this, parkin null-mutant mice exhibited normal behaviour and brain morphology, with no loss of dopaminergic neurons. Dopamine levels were altered, suggesting a possible role in dopamine regulation (Goldberg et al. 2003). Drosophila parkin null-mutants showed a consistent pattern of pathology, with locomotor deficits, sterility and decreased lifespan (Greene et al. 2003). These were attributed to mitochondrial dysfunction, which is also a feature of PD (see below). Research into the potential toxic effects of accumulation of parkin substrates has been inconclusive (Betarbet et al. 2005). Evidence points to parkin involvement in the pathogenesis of PD, but mutations of this protein are not sufficient alone to cause the disease.
A missense mutation for the gene encoding the protein UCH-L1 has been detected in autosomal dominant familial cases of PD in Germany (Leroy et al. 1998). In sporadic cases of PD, UCH-L1 is downregulated and oxidized in the cerebral cortex (Choi et al. 2004), the significance of this is unknown. UCH-L1 mutations in mice produce neuromotor signs that are not typical of PD, and are characterised as Gracile Axonal Dystrophy mice (GAD). As for parkin, the evidence confirms some involvement in PD pathogenesis of these elements of the UPS, but points to the need for further research to fully deduce their role.
Other genetic mutations have been identified, such as LRRK2 (a kinase;Zimprich et al. 2004) and DJ-1 (aka PARK 7), which is involved in a similar protein degradation pathway (SUMO; Bonifati et al. 2003).
It is tempting to attribute the accumulation of ï¡-synuclein to a decrease in activity of the UPS, but evidence that ï¡-synuclein is a substrate of this system is contradictory (Paxinou et al. 2001), with results differing between in vitro cell lines and conditions. Some studies suggest that ï¡-synuclein accumulation may inhibit the UPS, resulting in further protein accumulation (Liu et al. 2005).
A significant amount of evidence supports the hypothesis of involvement of the UPS in PD aetiology. In familial cases genetic mutations have been discovered that account for a portion of the susceptibility to, and pathogenesis of PD; but other factors are obviously required for both early onset and sporadic cases to develop. UPS activity has been found to be lowered in sporadic PD patients, with impaired proteasomal activity and reduced expression of subunits in the substantia nigra (McNaught et al. 2003). Whether UPS impairment is a primary cause or secondary to another event is not yet clear. Some researchers believe that the mechanism underlying the dysfunctional UPS may involve mitochondrial dysfunction, which has also been implicated in other neurodegenerative diseases (Hashimoto et al. 2003). During energy production by respiration in the mitochondria, there is a continuous leakage of free radicals, such as reactive oxygen species (ROS), which are also released by inflammatory cells. Antioxidant mechanisms exist to mop these up before they can cause oxidative damage to surrounding molecules, such as proteins, lipids and DNA, but these are not 100% efficient. This results in a gradual increase in damaged cellular components with aging (Vigoroux et al. 2004). Higher levels of oxidization products have been found in brain tissue of patients with neurodegenerative diseases such as PD (Dexter et al. 1994) and suggest an important role for free radicals in its aetiology. Mitochondrial DNA (mtDNA) damage has been hypothesised to accumulate, leading eventually to mitochondrial dysfunction, which further increases free radical leakage. Mitochondrial complex I, in particular, has been implicated. Induced parkinsonism in animal models using the pesticide rotenone has been shown to inhibit mitochondrial complex I (Sherer et al. 2002). Administration of MPTP also induces PD symptoms and inclusion body formation, via the complex I inhibition of its metabolite MPP+ (Ramsay et al. 1986). This has been recorded in human subjects following the use of illicitly manufactured narcotics, in which MPTP is produced as a contaminant, but has now been used to reliably induce disease in rodents to further knowledge of the pathogenesis of this disease. As well as providing valuable insights into the mechanisms underlying PD, the ability of chemicals to produce the symptoms and pathology of PD has also raised concerns about the role of environmental factors in the aetiology of the sporadic disease. Some epidemiological studies have linked pesticide exposure to an increased risk of developing PD (Park et al. 2005), as well as suggestions that increased coffee/caffeine consumption and smoking (Wirdefeldt et al. 2005) may have some protective benefits. Exposure to heavy metals, such as manganese has also shown a correlation with PD in some studies, but not all. Heavy metals are known to accelerate free radical formation and hence increase oxidative stress, so it would not be unexpected if higher levels were involved in PD aetiology. Results of epidemiological studies that claim to prove these positive and negative correlations with PD are contradictory, and further research is required, which could also take diet into account (particularly ingested antioxidant levels and lifestyle).
Mitochondrial dysfunction may cause a decrease in UPS activity, either by reduced ATP production, which is essential for many processes of the pathway, and/or by increasing oxidative stress and damaging vital components of the system (Fahn & Salzer 2004). The pivotal role of mitochondria has been elegantly demonstrated by the use of cytoplasmic hybrids. These ‘cybrids’ are formed by taking mtDNA from platelets of patients with PD and inserting it into cultured human neuroblastoma cells that have been depleted of their endogenous mtDNA. These neuronal cells faithfully recapitulate the structure and antigenicity of Lewy bodies (Trimmer et al. 2004), and similar studies have reported other pathogenic features consistent with a role for mitochondria and oxidative stress in PD.
It is now widely accepted that oxidative stress is a contributory factor to PD aetiology, with markers of oxidative damage found to be higher than in non-PD controls.
Antioxidants have been administered in a number of studies to further explore the impact of free radicals and therapeutic/prophylactic options. Transgenic mice that overexpress the endogenous antioxidant Cu,Zn-superoxide dismutase did not show any symptoms or DA neuron loss following exposure to paraquat (herbicide)-maneb (fungicide), compared to non-transgenic controls (Thiruchelvam et al. 2005). Studies involving exogenous antioxidants have produced inconclusive results, and more research is required in this area.
The specificity of dopaminergic neuronal loss, mainly in the substantia nigra pars compacta, in PD is replicated in chemically induced animal models of disease. The reason for this consistent and specific pattern of neuropathology may be due to the oxidation properties of DA, with highly reactive DA-quinones being generated. These are able to form complexes with ï¡-synuclein and may inhibit mitochondrial complex I (Asanuma et al. 2003). This has important implications for the commonly used L-DOPA therapy, which may also contribute to neurodegeneration.
Some researchers also believe that inflammation may play a role in PD, as microglial cells proliferate in affected brain regions (McGeer & McGeer 2004).
The aetiology of Parkinson’s Disease is multifactorial, with a combination of genetic, environmental and possibly immunological factors, many of which are still unknown or poorly understood. There is growing evidence from a variety of research techniques that oxidative stress, mitochondrial dysfunction and deficits in protein degradation pathways, such as the UPS are interlinked. The aetiological factors initiate a process that culminates in the accumulation and aggregation of proteins, mainly ï¡-synuclein, in dopaminergic neurons of the nigrostriatal system, which leads to cell-death. Further research is required to fully elucidate the precise molecular mechanisms that underlie the neuropathology of PD, so that effective treatments or prophylactic advice can be established.
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