Monoamine Transporter Pathologies 185 7 Parkinson’s Disease (PD) Parkinson’s disease (PD) is characterized by rigidity in movement, resting tremor, bradykinesia, and difficulty in maintaining postural stability (Gelb et al., 1999). PD is a neurodegenerative disease marked by Lewy bodies or abnormal protein aggre- gates and the loss of dopaminergic cells in the substantia nigra (Gelb et al., 1999). These dopaminergic neurons project into the striatum. Disruption of these neural circuits inhibits pathways responsible for controlling movement. The cause of PD is generally unknown. However, the progressive loss of dopaminergic neurons has led researchers to examine the role of the dopamine system in PD. Postmortem studies show a correlation between PD and DAT concentrations in the striatum (Niznik et al., 1991). Molecular imaging techniques have been used to determine DAT levels using DAT radiotracers such as 2β-carbomethoxy-3β- (4-iodophenyl) tropane ([ 123 I] β-CIT) and [ 11 C] cocaine (Shih et al., 2006). These techniques are useful for the evaluation and diagnosis of patients with PD and to monitor the progression of the disease (Shih et al., 2006). The delivery of DA to surviving nerve terminals by treatment with L -DOPA helps alleviate some of the early symptoms of PD (Nutt, 2002). Unfortunately, the ameliorating effects of L -DOPA fade and within five years of treatment approximately half of patients display involuntary, sometimes debilitating dyskinesias (Bezard et al., 2001). This reduced ability of L -DOPA to treat patients is thought to result from a failing ability to store synthesized DA (Lee et al., 2008). The reduction in the ability to store DA is thought to result from the immediate release of all DA synthesized from L -DOPA (Lee et al., 2008). Lee and colleagues demonstrated that the sprouting of DA termi- nals and decreased DAT function help to prevent the appearance of PD symptoms until approximately 60% of dopaminergic neurons in the substantia nigra are lost (Lee et al., 2008). They proposed that the DA terminal sprouting and decreased DAT function helped contribute to the DA release responsible for the reduced therapeutic benefits of L -DOPA (Lee et al., 2008). 8 Important Findings and the Need for Future Studies Significant advances have been made in understanding the role of the monoamine transporters in the pathology of disease states. Despite these advances, studies are needed to further elucidate monoamine transporter structure and function. In recent years, genetic animal models exhibiting disruption of the monoamine transporters have provided a unique method for investigating the role of these transporters in physiology and pathology. Studies with DAT, SERT, and NET knock-out mice are able to reveal subtle interplay among these transporters (Gainetdinov and Caron, 2003). Knock-out of individual transporters exposes secondary functions and compensatory mechanisms of the remaining monoamine transporters. The development of improved pharmacological agents targeting the monoamine transporters has been hindered by a lack of structural information. Although numer- ous biochemical and molecular studies have provided insight into the structural and 186 N.R. Sealover and E.L. Barker mechanistic aspects of monoamine transporter function, to date no crystal struc- ture exists. Yamashita and colleagues provided a significant contribution to the field with the crystallization of LeuT Aa (Yamashita et al., 2005) and further information was revealed with the subsequent cocrystallization of LeuT Aa with the TCAs (Singh et al., 2007; Zhou et al., 2007). These structures have allowed for homology mod- eling of the monoamine transporters and have revitalized the structural studies of these transporters (Indarte et al., 2008; Jorgensen et al., 2007a, b; Celik et al., 2008; Forrest et al., 2007; White et al., 2006). Important discoveries have been made in the findings of transporter gene poly- morphisms. The identification of promoter polymorphisms and coding region polymorphisms in individuals has helped to link these variations with disease states. Further studies are needed to understand the genetic and environmental contribu- tions of these variants to disease. Additionally, a number of regulatory mechanisms and interacting proteins have been identified for the monoamine transporters. Future studies will need to identify additional players in this complex network of interac- tions. A greater understanding of this network will be vital in understanding and treating diseases such as addiction, ADHD, autism, and PD. 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