Send Orders of Reprints at bspsaif@emirates.net.ae CNS & Neurological Disorders - Drug Targets, 2012, 11, 000-000 1 1871-5273/12 $58.00+.00 © 2012 Bentham Science Publishers C. elegans as a Genetic Model System to Identify Parkinson's Disease- Associated Therapeutic Targets Julia Vistbakka 1,§ , Natalia VanDuyn 2,§ , Garry Wong 1 and Richard Nass *,2 1 Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland, Yliopistoranta 1, Kuopio 70210, Finland 2 Indiana University School of Medicine, Indianapolis, Indiana, USA Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and the selective loss of dopaminergic neurons. The etiology of idiopathic PD is likely a combination of genetic and environmental factors. Despite findings from mammalian studies that have provided significant insight into the disorder, the molecular mechanisms underlying its pathophysiology are still poorly understood. The nematode Caenorhabditis elegans (C. elegans) is a powerful system for genetic analysis. Considering C. elegans short lifespan, fully sequenced genome, high genetic and neurobiochemical conservation with humans, as well as the availability of facile genetic tools, the nematode represents a highly efficient and effective model system to explore the molecular basis of PD. In this review we describe the utility of C. elegans for PD research, and the opportunity the model system presents to identify therapeutic targets. Keywords: Nematode, dopamine, Parkinson’s disease, neurodegeneration, neuroprotection. 1. INTRODUCTION 1.1. Parkinson’s Disease Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder affecting approximately 1-2% of the population over the age of 50 [1- 3]. PD has a peak age of onset at approximately 60 years of age, and the prevalence increases approximately two-fold at age 75 years [4-6]. PD is characterized by rhythmic shaking and involuntary movement (tremor-at-rest), slowness of movement (bradykinesia), increased muscle tone (rigidity), and loss of postural reflexes [4, 7]. While the motor symptoms largely dominate the clinical picture of PD, patients also develop a range of non-motor dysfunctions. These symptoms include orthostatic hypotension, dementia, depression, and sleeping disorders [8]. These non-motor features arising from extranigral neuronal losses can be an additional source of considerable consternation and disability [9]. A molecular hallmark of PD is the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) [1, 3, 10, 11]. In idiopathic PD the symptoms become apparent when more than 70% of the striatal and 50% of the nigral DAergic neurons are lost [12]. Neurodegeneration also occurs in other areas of the brain including the dorsal motor nucleus of the vagus, locus ceruleus (LC), and olfactory nuclei. The neuropathology is often accompanied by the presence of fibrillary cytoplasmic inclusions called Lewy bodies (LBs) and Lewy neuritis *Address correspondence to this author at the Indiana University School of Medicine, 635 Barnhill Dr., MS 549, USA; Tel: ????????????????????; Fax: ???????????????????; E-mail: ricnass@iupui.edu § Authors contributed equally to the manuscript. (LNs) [13]. LBs and LNs contain the presynaptic protein - synuclein and ubiquitin protein deposits, which occur in dead or dying dopamine-producing neurons in the SNpc as well as the LC and other regions of the nervous system, including the cortex, limbic areas, and central and peripheral divisions of the autonomic nervous system [3, 4, 8, 12, 14]. Pathological confirmation upon autopsy has been the standard criterion for PD diagnosis with the observation of LBs in association with neuronal loss in the SN. However, LBs are also detected in brains of individuals with a range of other non-Parkinsonian clinical syndromes, including dementia with LBs, Alzheimer’s disease, and Gaucher disease [13]. Furthermore, a mutation in the protein parkin, a component of the multiprotein E3 ubiquitin ligase complex that can cause recessive juvenile PD, and one of the more prevalent PD-associated mutations, is not generally associated with development of LBs, limiting the utility of LBs as a diagnostic tool. Etiological and pathological evidence suggest that there are both genetic and environmental components that contribute to the development of PD [2, 4, 10]. The vast majority of PD cases are sporadic, however approximately 15-20% of patients have a known family history of the disease [11]. PD is more common in rural areas, and increased rates of the disorder are associated with the use of pesticides and herbicides [15, 16]. Rare familial forms of PD provide insight into the pathophysiologic mechanisms of the disorder. Current studies indicate that there are at least 16 loci and 11 genes associated with the development of PD [17]. Genetic studies suggest that oxidative stress, mitochondrial dysfunction, protein aggregation and proteasome dysregulation play integral roles in PD- associated cell death [18]. In the early stages of PD the symptoms generally respond well to therapeutics that enhance the levels of dopamine