Etiology of Parkinsons Disease

Etiology of Parkinsons DiseaseParkinsons Disease is the mo most plebeian neurodegene gitive unhealthiness, after Alzheimers. Onset typically occurs late in life, affecting approximately 1% of 65 year olds, with the prevalence increase to 4-5% by age 85 (Dawson Dawson 2003). There atomic egress 18 withal out of date cases of early- blast Parkinsons, which are usually familial. Research into the gene innovations discovered in much(prenominal) hereditary cases has also contri thated to the understanding of the aetiology of the spontaneous, late onset pass water of the disease.Parkinsons Disease (PD) is characterized clinically by tremors at rest, bradykinesia (s first-class honours degreeness of voluntary movement), muscular tissue rigidity, hang in postural reflex and facial expression and an change gait (Kumar et al. 2005). A subset of patients (10-15%) also develop dementia. Symptoms are progressive and depart in reducingd mobility and razetually severe disability.The symptomatic motor disturbances build up from the progressive redness of dopaminergic neurons in the substantia ringtail of the brain. This results in a decrease in the dopaminergic content of the striatum. These areas play an important fibre in modulating feedback from the thalamus to the motor cortex.AIMS AND OBJECTIVESThis report aims to investigate the current knowledge of the aetiology of PD, by examining depict in the literature. It is crucial to understand the pathological mechanisms rudimentary the selective wipeout of dopaminergic neurons in PD so that potent treatments and prophylaxis can be developed.PROPOSED administrationResearchers prolong studied the molecular mechanisms of PD pathogenesis utilize a cast of techniques in vitro tissue cultures of forgiving and animal neurons, post-mortem human brain tissue, mouse models of the disease, genetic studies and more novel techniques much(prenominal) as the use of cybrids. rise from all of these will be amal gamated and conclusions drawn.MOLECULAR PATHOGENESIS OF PDThat PD is generally associated with old age must be considered an important jot when trying to elucidate the causal mechanism of PD. The same is also dead on target of the most common neurodegenerative disease, Alzheimers Disease (AD). Both are also characterised by an assembly of protein aggregates resulting in progressive neuronal loss, suggesting a common key pathology.Histological brain sections of PD patients shows characteristic, large cellular inclusion bodies in the cytosol of surviving neurons of the substantia nigra, as well as locus ceruleus and surrounding brain stem nuclei, called Lewy bodies (Kumar et al. 2005). These are aggregates of -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 former(a) proteins much(prenominal) as ubiquitin and synphilin-1. It is undecipherable whether these aggregates contri thoe 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). just nearly evidence has recently been produced by Setsuie and colleagues (2005), utilize a PD rat model in which proteasome preventors caused inclusion shaping, which resulted in decreased dopaminergic neuronal shoemakers last that normally follows 6-hydroxyl dopamine (6-OHDA) administration.Lewy bodies are also nominate in low numbers in normal aging and AD (Jellinger 2001). However, Lewy bodies are non found in some cases of puerile 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 much(prenominal) as rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or transgenic mice that overexpress human SYN gene (for -synuclein) mutations, do not faithfully replicate the social 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.Role of the ubiquitin-proteasome formation (UPS)Although the precise quality of Lewy bodies in the pathogenesis of PD is lighten unclear, the accumulation and aggregation of proteins suggests that there is a deficit in the cellular systems that normally remove and degrade brachydactylous 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 rele ase ubiquitin monomers back into the system (Alberts et al. 2002). Ubiquitination and cite 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 take a leak revealed evidence that this system is involved in PD aetiology, which has aided the understanding of the pathogenesis of noncontinuous 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 assume a neuroprotective occasion (Petrucelli et al. 2002). Despite this, parkin null-mutant mice butt againsted normal behaviour and brain morphology, with no loss of dopaminergic neurons. dopamine levels were altered, suggesting a possible mapping in dopamine regulation (Goldberg et al. 2003). drosophila parkin null-mutants showed a undifferentiated pattern of pathology, with locomotor deficits, sterility and decreased lifespan (Greene et al. 2003). These were attributed to mitochondrial disfunction, which is also a feature of PD (see below). Research into the potential virulent 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 noetic cortex (Choi et al. 2004), the significance of this is unknown. UCH-L1 mutat ions 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 fatality for further enquiry to fully deduce their role.Other genetic mutations digest been identified, such as LRRK2 (a kinaseZimprich et al. 2004) and DJ-1 (aka PARK 7), which is involved in a analogous protein degradation pathway (SUMO Bonifati et al. 2003).It is tempting to attribute the accumulation of -synuclein to a decrease in activity of the UPS, but evidence that -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 -synuclein accumulation whitethorn inhibit the UPS, resulting in further protein accumulation (Liu et al. 2005).Role of mitochondrial dysfunction and oxidative assayA significant amount of evi dence supports the supposal 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 unavoidable 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 other 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 innates, such as reactive atomic number 8 species (ROS), which are also released by inflammatory cells. Antioxid ant 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(prenominal) 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 bullet (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 pelt along free radical formation and hence increase oxidative stress, so it wou ld 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 change magnitude 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 form by taking mtDNA from platelets of patients with PD and inserting it into cultured human neuroblastoma cells that have been humble of their endogenous mtDNA. These neuronal cells faithfully recapitulate the structure and antigenicity of Lewy bodies (Trimmer et al. 2004), and similar stud ies 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 spe cific pattern of neuropathology may be due to the oxidation properties of DA, with exceedingly reactive DA-quinones being generated. These are able to form complexes with -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).CONCLUSIONThe aetiology of Parkinsons 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 aggrega tion of proteins, mainly -synuclein, in dopaminergic neurons of the nigrostriatal system, which leads to cell-death. 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