Parkinson’s Disease and Parkin: Insights from Park2 Knockout Mice

Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder distinguished by resting tremor, bradykinesia, rigidity, postural instability and gait disturbances. Non-motor symptoms including dysfunction of the autonomic nervous system, neuropsychiatric changes, sensory and sleep disturbances are also common. PD may be diagnosed at any age but is most common in aged populations affecting approximately 1% of individuals over 60 years of age and rising to approximately 4% in age groups above 85 years of age (de Lau and Breteler, 2006; Van Den Eeden et al., 2003). It has become apparent that differential subgroups may be categorised by age of onset, dominant symptoms and progression. Two key subsets include lateand early-onset PD. Late-onset PD is typically identified in individuals over the age of 70 and is characterised by postural imbalance and gait impairment with accompanying rigidity and akinesia. Early-onset PD is typified by a dominant tremor and slow progression in motor decline, and is primarily identified in individuals less than 50 years of age (Lewis et al., 2005; Selikhova et al., 2009). The lead pathological identifier of PD is moderate to severe dopaminergic neuronal loss within the substantia nigra pars compacta with accompanying Lewy pathology in surviving neurons (Daniel and Lees, 1993; Dickson et al., 2009; Gelb et al., 1999). It is thought that the combination of Lewy pathology and dopaminergic cell loss in PD leads to striatal dopamine depletion, and this accounts for the motor symptoms (Obeso et al., 2008). Earlier diagnosis of PD is important as motor symptoms do not become apparent until approximately 60% of dopaminergic neurons are lost (Fearnley and Lees, 1991; Pakkenberg et al., 1991). Current treatments are available to manage the symptoms of PD. Medications such as the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) and inhibitors of dopamine metabolism are used to supplement the reduced dopamine level. Deep brain stimulation is an alternative treatment. The patient undergoes surgery to implant an electrical stimulation device into the affected region of the basal ganglia. The electrical impulses generated by the device interfere with the abnormal signals that are causing the tremor, thereby alleviating some of the symptoms of the disease (reviewed in (Hurelbrink and Lewis, 2010)). To identify treatments that address or arrest the progressive nature of PD, an understanding of the molecular mechanisms responsible for the loss of nigrostriatal dopaminergic neurons and associated Lewy pathology must be delineated.