The role of parkin in Parkinson’s disease: a stem cell perspective

Abstract

ISSN 1758-2024 10.2217/NMT.12.25 © 2012 Future Medicine Ltd Neurodegen. Dis. Manage. (2012) 2(3), 239–241 part of Parkinson’s disease (PD) is a movement disorder characterized by the degeneration of nigral dopaminergic (DA) neurons. The defining locomotor symptoms (i.e., rest tremor, rigidity, bradykinesia and postural instability) are caused by a relatively selective loss of nigral DA neurons [1]. Current pharmacological treatments focus on augmenting DA levels in the brain (e.g., levodopa, monoamine oxidase [MAO]-B inhibitors and catechol-O-methyltransferase inhibitors) or mimicking the actions of DA (e.g., DA agonists). These drugs mostly provide symptomatic relief; the unabated degeneration of nigral DA neurons and other cells invariably kills PD patients. Surgical interventions such as deep-brain stimulation are similar in that they only alleviate locomotor symptoms and have no impact on the neuro degeneration process. Thus, the central problems for PD research are to understand the cause for the degeneration of nigral DA neurons and to identify a strategy to intervene, preferably as early as possible. Mechanistic studies on PD-linked monogenic mutations have revealed significant insights into the unique vulnerabilities of nigral DA neurons and how mutations of a single gene, such as parkin, expose these vulnerabilities. A variety of mouse genetic models of PD have revealed surprisingly little information on the human disease [2]. For example, parkin knockout mice do not exhibit any robust phenotype [3], in sharp contrast with PD patients with parkin mutations [4]. It suggests that human nigral DA neurons are quite different from the murine counterpart. The landmark discovery of induced pluripotent stem cells (iPSCs) [5,6] has made it possible for us to generate patient-specific midbrain DA neurons from PD patients with parkin mutations and normal controls [7]. Our study shows that parkin mutations significantly disrupt the precision of DA transmission by increasing spontaneous DA release and decreasing DA reuptake. In addition, parkin mutations greatly elevate DA-induced oxidative stress by increasing the transcription of MAOs, which catalyze the oxidative deamination of DA – a reaction that produces a large amount of reactive oxygen species. Overexpression of wild-type parkin, but not its PD-linked mutant, significantly rescues all these phenotypes. Thus, mimicking the beneficial actions of parkin, for example, with small-molecule