**1. Introduction**

46 Etiology and Pathophysiology of Parkinson's Disease

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Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic

Evolutionary toggling of the *MAPT* 17q21.31 inversion region. Nature Genetics, 40

Parkinson's disease (PD) is the most common neurodegenerative movement disorder affecting millions of predominantly elderly individuals worldwide. Originally described as "The Shaking Palsy" in 1817 by the British physician, James Parkinson, the disease is attended by a constellation of motoric deficits including bradykinesia (slowness in movements), postural instability, rigidity and tremor that ultimately result in near total immobility. Although pathological changes are distributed in the PD brain, the principal neuropathology that underlies the characteristic motor phenotype of PD patients is unequivocally the loss of midbrain dopaminergic (DA) neurons in the *substantia nigra pars compacta* (SNpc), which results in a severe depletion of striatal dopamine and thereby an impaired nigrostriatal system that otherwise allows an individual to execute proper, coordinated movements. This specific pattern of neurodegeneration in PD is often accompanied by the presence of eosinophilic intracytoplasmic inclusions known as Lewy bodies (LBs) in surviving neurons in the SN as well as in other affected brain regions such as the dorsal motor nucleus of the vagus, locus ceruleus (LC) and olfactory nuclei (Braak et al., 2003). In advanced stages of the disease, LB pathology can also be found in the limbic structures and neocortex (Braak et al., 2003). Nonmotor features arising from these extra-nigral neuronal lesions, including autonomic, sensory and cognitive dysfunctions, present additional sources of considerable consternation and disability for affected individuals (Olanow et al., 2008). Thus, although SN pathology is often regarded as the most important hallmark of PD, the disease is increasingly being recognized as a multi-system disorder affecting not only dopaminergic, but also noradrenergic, cholinergic and serotonergic systems (Alexander, 2004).

Despite intensive research, the etiology of PD remains poorly understood and no current treatments can unequivocally slow or stop the degenerative process. Current therapies for PD are palliative at best and the mainstay is pharmacologic intervention via DA replacement (e.g. through L-DOPA administration). Major drawbacks with current therapies include the inevitable loss of effectiveness and increasing drug-induced side effects as the disease progresses. Invariably, the debilitating nature and morbidity of the disease present significant healthcare, socio-economic and emotional problems. As the world population rapidly ages, these problems undoubtedly would also increase. Notably, a recent study by Dorsey et al projected that the number of PD cases in Europe's five most

Parkin and Parkinson's Disease 49

Apart from these, mutations in *UCHL1*, *Omi/HtrA2* and *ATP13A2* have also been suggested to cause parkinsonism, but their relevance to PD is currently unclear because the purported disease-causing mutation is either extremely rare in occurrence (e.g. UCHL1 I93M) (Healy et al., 2004) or present in control population at similar frequencies (e.g. Omi/HtrA2 G399S) (Simon-Sanchez and Singleton, 2008) or otherwise results in a clinical phenotype that is rather divergent from classical PD (e.g. ATP13A2-linked parkinsonism that is characterized by mild parkinsonism and prominent cognitive defects) (Ramirez et al., 2006). More recently, two other genes, *PLA2G6* encoding a phospholipase and *FBXO7* encoding a component of the Skp-Cullin-Fbox (SCF) ubiquitin ligase complex, have also been identified to be associated with recessive parkinsonism (Di Fonzo et al., 2009; Paisan-Ruiz et al., 2009). The function of these various disease-associated genes, especially the unequivocal ones, has been extensively characterized. Interestingly, it turned out that these seemingly functionally disparate PD-linked proteins that have no clear relationship with each other at first glance may all influence either protein or mitochondrial homeostasis, with some, like parkin, being directly involved in both. Accordingly, in the absence of functional parkin, aberrations in both protein and mitochondrial quality control (QC) would ensue that may eventually trigger the demise of susceptible neurons. Indeed, the pivotal role parkin plays in maintaining DA neuronal survival is underscored by our current recognition that parkin dysfunction represents not only a predominant cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of PD. Here, we shall discuss the role of parkin in PD and why a better understanding of parkin function can help elucidate

Mutations in parkin were originally identified in Japan more than a decade ago to be causative of autosomal recessive juvenile parkinsonism (ARJP) (Kitada et al., 1998). Following this discovery, several ethnically diverse individuals with early-onset PD (age < 45 years) in other parts of the world were also found to carry parkin mutations, which occur at a frequency of about 10-20% and 50% in sporadic and familial early-onset cases respectively (Lucking et al., 2000; Mata et al., 2004; Periquet et al., 2003). Clinically, parkin-associated parkinsonism is often quite indistinguishable from idiopathic PD, with bradykinesia, rigidity and rest tremor being variably combined in both disorders. However, parkin-related patients tend to exhibit slower disease progression and better response to L-DOPA (and also a higher tendency to develop L-DOPA-induced dyskinesia) than those with parkinsonism of different etiologies. Additionally, other less typical features common to parkin cases include prominent dystonia, presence of hyperreflexia and more symmetrical presentation of symptoms, although none of these features are sufficiently specific to be diagnostic of parkin mutations. Limited post-mortem studies of known parkin cases conducted to date demonstrated neuronal loss predominantly in the SN and LC regions of the brain that is accompanied by gliosis. Importantly, the majority of parkin-related cases are devoid of classic LBs (Hayashi et al., 2000; Mori et al., 1998; Pramstaller et al., 2005), suggesting that parkin-associated parkinsonism is pathologically distinct from idiopathic PD, and as such may represent a phenocopy of the latter. However, this is debatable as LBs are found in at least two cases of parkin-related PD (Farrer et al., 2001; Pramstaller et al., 2005). An attractive corollary to this is that functional parkin may facilitate LB formation, which we favor as a working hypothesis (see section

potential therapeutic strategies for the disease.

**2.1 Parkin mutations and parkinsonism** 

2.2).

and the world's ten most populous countries would increase to 9 million in year 2030 (Dorsey et al., 2007). This is definitely a worrying trend, and one that aptly emphasizes the urgency to develop more effective treatment modalities for the PD patient.

In large part, the difficulty in identifying disease-modifying drugs for PD is due to: i) our current limited understanding of the molecular mechanism(s) that underlies the pathogenesis of PD (the illumination of which would allow the identification and therapeutic exploitation of key molecules involved in the pathogenic process), and ii) the lack of a truly representative mammalian model of PD that recapitulates accurately the progressive process as well as the nature and distribution of the human pathology. However, during the last decade or so, the identification and functional characterization of several genes whose mutations are causative of rare familial forms of PD have provided tremendous insights into the molecular events underlying neurodegeneration in PD. Alongside, several genetic models of PD have also been generated that replicate the disease phenotype to varying degrees of success. Collectively, these studies implicate aberrant mitochondrial and protein homeostasis as key contributors to the development of PD, with oxidative stress likely acting an important nexus between the two pathogenic events.
