Content
- Introduction
- Genetic Markers of Parkinson's Disease
- Alpha-synuclein
- Parkin
- PARK7/DJ-1
- PARK6/Pink1
- UCH-L1, Tau and others
- Summary
- References
1. Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease. Unlike the broad spectrum of neuronal phenotypes affected in Alzheimer’s, one neurotransmitter, dopamine (DA), is primarily diminished in PD. The DA depletion arises from the nearly selective loss of DA-producing neurons in the substantia nigra, which project primarily to the dorsal striatum (caudate and putamen). The degeneration of nigrostriatal pathway causes rigidity, tremor, postural instability and difficulty initiating movements. Although DA replacement therapy can alleviate some of the motor symptoms of PD, there are currently no treatments proven to slow or halt the progressive degeneration of the nigral dopaminergic neurons or other brain nuclei affected in PD, such as the locus coeruleus. Therefore, the clinical symptoms of PD worsen with age.
Upon autopsy, in addition to a profound loss of neuromelanin-containing nigral neurons, round cytoplasmic inclusions called Lewy bodies are found in some remaining neurons in the substantia nigra, and frequently elsewhere in the brain. The presence of nigral Lewy bodies is required for diagnosis of PD, and has traditionally been observed by eosin staining or by immunohistochemistry using ubiquitin or UCH-L1 (PGP9.5) antibodies.
Despite intensive research, the cause of PD remains uncertain. Not long ago, PD was widely considered to be a non-genetic disease, however, many families have been identified that show a Mendelian pattern of inherited parkinsonism. The recent identification of several genes with mutations linked to familial forms of PD has provided opportunities to investigate the cellular and molecular mechanisms of PD pathogenesis. Although mutations in some of these genes are rare, it is likely that the proteins they encode are involved in the more common idiopathic PD. In certain populations, mutations in some genes have recently been found to account for a much larger fraction of PD cases than suggested by the initial reports (Hatano et al., 2004; Klein et al., 2005; Lesage et al., 2006; Lucking et al., 2000; Ozelius et al., 2006).
Pathways of Parkinson's Disease |
2. Genetic Markers of Parkinson's Disease
Alpha-synuclein
Point mutations in alpha-synclein (PARK1) were the first to be linked to autosomal dominantly inherited PD (Kruger et al., 1998; Polymeropoulos et al., 1997). Subsequently, immunohistochemical studies with alpha-synclein antibodies revealed that aggregated alpha-synclein is a major component of Lewy bodies, thus implicating alpha-synclein in both familial PD and the more common non-inherited PD (Spillantini et al., 1997). Since then, a-synclein immunohistochemistry has replaced ubiquitin immunohistochemistry and eosin staining as the method of choice for observing Lewy bodies and thus diagnosing PD pathologically. Alpha-synclein immunoreactivity is widespread in normal brains, however, antibodies that specifically recognize alpha-synclein that is phosphorylated at serine 129 specifically stain synucleinopathy lesions (Fujiwara et al., 2002). Although much remains to be learned about the function of a-synclein and the exact mechanisms by which the originally identified point mutations cause PD, the recent discovery that wild-type alpha-synclein gene duplication and triplication mutations can cause early onset familial PD strongly suggests that elevated levels of alpha-synclein lead to protein aggregation, Lewy pathology and PD (Singleton et al., 2003). Indeed, overexpression of wild-type alpha-synclein has been shown to cause synuclein pathology and behavioral deficits in flies, mice and rats (Feany and Bender, 2000; Kirik et al., 2002; Lo Bianco et al., 2002; Masliah et al., 2000).
Parkin
A variety of deletion and insertion mutations, point mutations and truncation mutations in the Parkin gene have been linked to recessive parkinsonism at the PARK 2 locus and loss-of-function parkin mutations appear to be a major cause of early-onset PD (Kitada et al., 1998; Lucking et al., 2000). Although initial reports indicated an absence of Lewy bodies in patients bearing parkin mutations, Lewy body pathology has since been reported in cases of parkin-linked PD (Farrer et al., 2001; Pramstaller et al., 2005). Parkin functions as an E3 ubiquitin ligase which mediates the covalent attachment of ubiquitin to various protein substrates (Shimura et al., 2000). Many parkin binding proteins and substrates of parkin’s E3 ubiquitin ligase activity have been reported including CDCrel-1, synphilin-1, glycosylated a-synclein, cyclin E, tubulin, Pael-R, synaptotagmin XI, p38/JTV-1, CHIP and CASK/LIN-2 (Chung et al., 2001; Corti et al., 2003; Fallon et al., 2002; Huynh et al., 2003; Imai et al., 2002; Imai et al., 2001; Ren et al., 2003; Shimura et al., 2001; Staropoli et al., 2003; Zhang et al., 2000). Several parkin-deficient animal models have been reported which, surprisingly, do not recapitulate the pathology of humans bearing loss-of-function parkin mutations but which do show mitochondrial defects (Goldberg et al., 2003; Greene et al., 2003; Itier et al., 2003; Palacino et al., 2004; Pesah et al., 2004). This suggests that mitochondrial dysfunction may be an early event in PD pathogenesis, which is consistent with the fact that mitochondrial dysfunction has long been implicated in the etiology of idiopathic PD as well as parkinsonism induced by the neurotoxin MPTP. Loss of locus coeruleus neurons has been reported in parkin-deficient mice, consistent with the loss of these cells in patients bearing parkin mutations (Von Coelln et al., 2004) and in idiopathic PD. Interestingly, wild-type parkin has been shown to be sensitive to oxidative damage that can be caused by DA, suggesting that inactivation of parkin in DA-containing neurons may contribute to non-inherited PD (LaVoie et al., 2005).
PARK7/DJ-1
Loss-of-function mutations in DJ-1 cause recessive parkinsonism linked to the PARK7 locus (Bonifati et al., 2003). DJ-1 mutations are rare and autopsies have not yet been reported from patients bearing DJ-1 mutations, but presumably severe depletion of nigral DA neurons occurs. Although DJ-1 is highly conserved across many species from yeast to humans and it is expressed in most cell types, the function of DJ-1 remains uncertain. The primary sequence and crystal structures do not show homology to proteins of known function but the unusually high sensitivity of cysteine 106 to oxidation suggests that DJ-1 is a sensor for oxidative stress and in vitro studies suggest that DJ-1 can protect cells from death induced by oxidative stress (Canet-Aviles et al., 2004; Yokota et al., 2003). DJ-1-deficient mice show locomotor deficits, reduced responsiveness to activation of D2-type DA receptors and increased sensitivity to MPTP (Chen et al., 2005; Goldberg et al., 2005; Kim et al., 2005b). Neither mice nor drosophila deficient for DJ-1 show loss of dopaminergic neurons, however, they both provide in vivo evidence that DJ-1 can protect cells from oxidative stress (Kim et al., 2005b; Menzies et al., 2005; Meulener et al., 2005; Park et al., 2005; Yang et al., 2005). Drosophila models also reveal that DJ-1 negatively regulates PTEN and that DJ-1-deficiency leads to reduced phosphorylation of Akt (Kim et al., 2005a; Yang et al., 2005).
PARK6/Pink1
Loss-of-function PINK1 (PARK6) mutations have been linked to recessively inherited parkinsonism (Valente et al., 2004). The clinical presentation of patients with PINK1 mutations is indistinguishable from idiopathic PD (Albanese et al., 2005), and it will be important to obtain autopsy reports to determine whether there is overlapping pathology. The primary sequence of PINK1 shows homology to serine/threonine kinases and contains a mitochondrial localization motif at the N-terminus. Indeed PINK1 localizes to mitochondria and exhibits kinase activity (Beilina et al., 2005), however the cellular substrates of its kinase activity have yet to be identified. No animal models have yet been reported with PINK1 mutations, but PINK1-deficient animals and cells should be valuable for identifying the cellular targets of PINK1 and mapping their functional pathways. It seems likely that one or more mitochondrial proteins are regulated by phosphorylation by PINK1 and that, in the absence of functional PINK1, mitochondrial dysfunction leads to degeneration of nigral neurons and subsequent clinical symptoms of PD. The mitochondrial localization of PINK1 together with the finding that oxidative stress induces mitochondrial localization of DJ-1 (Canet-Aviles et al., 2004) adds further support to a growing body of data that mitochondrial dysfunction is an early and central event in PD pathogenesis (Beal, 2005).
PARK8/LRRK2
Dominantly inherited mutations in LRRK2 (PARK8) are the most common cause of PD identified so far and may account for a significant fraction of all PD cases among North African Arabs and Ashkenazi Jews (Lesage et al., 2006; Ozelius et al., 2006; Paisan-Ruiz et al., 2004; Zimprich et al., 2004). Several point mutations linked to late-onset PD have been identified in this gene that encodes a 286 kDa multidomain protein expressed through the brain and other tissues. Several autopsies have been reported from PARK8 families and the pathology varies, depending upon the mutation, from typical PD with Lewy bodies to nigral degeneration without Lewy bodies and in some cases tau pathology (neurofibrillary tangles) (Wszolek et al., 2004). The LRRK2 primary sequence reveals domains with homology to leucine rich repeat domains, a Ras-like GTPase and COR domain, a tyrosine kinase domain and a WD40 domain. Dominantly inherited mutations have so far been identified in all of these domains except the WD40 domain. In contrast to mutations in PINK1 which likely cause PD by a loss-of-function mechanism, the I2020T mutation within the kinase domain of LRRK2 has been found to increase the kinase activity of LRRK2 by 40% in vitro, suggesting that increased LRRK2 kinase activity causes PD (Gloeckner et al., 2006). The tau pathology observed postmortem in some cases suggests that hyperphosphorylation of tau, perhaps directly or indirectly by mutant LRRK2, could be involved in the pathogenic mechanism. Future studies in cell and animal models will hopefully reveal more details of LRRK2 function and dysfunction.
UCH-L1, Tau and others
An S18Y polymorphism in UCH-L1 (PGP9.5) is associated with a significant decrease in the risk of PD in Asian populations (Maraganore et al., 1999), while the I93M point mutation in UCH-L1 has been implicated as a cause of dominantly inherited PD (Leroy et al., 1998). This dichotomy may perhaps be explained by the discovery that UCH-L1 exhibits dual activities: a ubiquitin hydrolase activity and a ubiquitin ligase activity which are differentially affected by S18Y and I93M (Liu et al., 2002). These findings, coupled with the fact that UCH-L1 is also a major component of Lewy bodies, further implicate dysfunction of the ubiquitin proteasome pathway in PD.
Mutations in the gene coding for the microtubule associated protein Tau (MAPT) have been linked to frontotemporal demential with parkinsonism (FTD-17), a form of parkinsonism characterized by Tau-immunoreactive neurofibrillary tangles (Hutton et al., 1998). This implicates tau pathology in this form of parkinsonism and has prompted further investigations of mutations or polymorphisms in the MAPT gene that may be associated with idiopathic PD.
In contrast to the elevated Ab levels that result from presenilin and APP mutations linked to AD, no unified mechanism easily explains how mutations in PD linked-genes lead to PD. Nevertheless, in the short time that has elapsed since the first PD-linked mutations were identified, some common results have already emerged from many of the studies of PD-linked mutations in cellular and animal models. Mitochondrial dysfunction and oxidative stress are implicated by studies of mutant parkin, DJ-1 and PINK1, while protein aggregation and ubiquitin-proteasome pathway dysfunction are implicated in studies of a-synclein, parkin and UCH-L1. It is also tempting to speculate that abnormal phosphorylation, perhaps of a-synclein and tau, may result from PINK1 and LRRK2 mutations, especially given the extensive synuclein and tau pathology of some patients bearing mutations in LRRK2.
3. Summary
The recent breakthroughs in human genetics of PD provide the best opportunity ever to elucidate the molecular pathways involved in the disease. Given the genetic evidence that several more genes are likely to be identified with PD-causing mutations, the advance in our understanding of PD pathogenesis is almost certain to accelerate. We are still in the midst of a paradigm shift from categorizing PD as a largely non-genetic disease to recognizing an increasingly significant genetic basis of PD, at least among certain groups.
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4. References
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