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    • In addition we observed significantly elevated levels

    2018-11-02

    In addition, we observed significantly elevated levels of synapsin and dopamine in Parkin cultures, although the changes in PINK1 cells did not reach statistical significance when compared with control iPSC- or ESC-derived floor-plate mDA neurons. Increased DA levels may appear, in contrast to the well-known loss of DA in the adenosine receptor agonist of PD patients. While reduction in the PD brain may simply reflect the progressive loss of DA-producing neurons, there are data suggesting a reduction in DA levels or release in the remaining cells (Nguyen et al., 2011). Our HPLC data argue for an increase in intracellular dopamine levels in PD versus control iPSC-derived mDA neurons, which may be indicative of dysregulation of neurotransmitter release linked to changes in synaptic activity. In support of our findings, previous animal studies have also reported increased levels of DA and DOPAC in Parkin- and PINK1-deficient mice (Kitada et al., 1998). Alternatively, this could be due to a loss of ATP and the proton gradient, which determines the synaptic vesicle-to-cytosol equilibrium of DA. It will be important to address whether such changes are limited to the Parkin, or potentially, the PINK1 phenotype or reflect changes in other genetic or sporadic forms of PD at distinct stages of disease. It is tempting to speculate whether increased levels could contribute to the pathogenic cycle induced by mitochondrial dysfunction and ultimately lead to mDA neuronal cell death (Figure 6). Determining the role of α-synuclein in PD pathogenesis is complicated by the fact that the physiological role of α-synuclein is not fully known; nevertheless, studies have linked α-synuclein to a variety of functions including the regulation of synaptic membrane processes and regulation of neurotransmitter release (Davidson et al., 1998; Nemani et al., 2010). Notably, α-synuclein has also been found to act as a negative regulator of synaptic vesicle fusion and exocytotic DA release, and studies have found that its overexpression impairs DA transmission in the early phases of neurodegeneration (Gaugler et al., 2012; Platt et al., 2012). Along these lines, other groups have found that absent or mutated α-synuclein can affect the compartmentalization of presynaptic DA and alter DA storage-pool capacity (Abeliovich et al., 2000; Mosharov et al., 2006; Murphy et al., 2000; Yavich et al., 2004). Furthermore, phage display and nuclear magnetic resonance spectroscopy have revealed that synapsin Ia is a binding partner of α-synuclein, which suggests that their interaction may play a critical role in the release of neurotransmitters (Woods et al., 2007). These results indicate that increased intracellular levels of DA observed in PD iPSC mDA neurons could be related to vesicular trafficking defects caused by α-synuclein protein dysfunction and other synaptic changes. Increased reactive oxygen species (ROS) resulting from defective mitochondria in PD mDA neurons may trigger destruction of synaptic vesicles, disrupt proper encapsulation of DA within vesicles, and cause the loss of the proton gradient required for synaptic vesicles to accumulate DA against its concentration gradient. Such abnormal DA homeostasis could eventually perpetuate a cascade of oxidative stress within already vulnerable cells.
    Experimental Procedures
    Author Contributions
    Introduction Human induced pluripotent stem cells (hiPSCs) are remarkable for their ability to self-renew and differentiate into various tissues and cell types (Takahashi and Yamanaka, 2006). Differentiation of these cells into a specific cell type allows for in-depth study with the goal of cell replacement therapy for neurodegenerative diseases such as Parkinson\'s disease (PD), which is caused by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta in the midbrain (Xu et al., 2013b). Expanding our knowledge of the cellular and molecular factors involved in the maturation and differentiation of human-derived neurons will significantly boost our ability to manipulate and generate specific cell types for disease therapy.