3 Parkin and Parkinson ’ s Disease

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