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    • Based on the differentially expressed key components

    2018-10-24

    Based on the differentially expressed key components and increase of intracellular iron in FTD3 neurons, we present an additional pathological feature of FTD3, which is associated with an imbalance in iron homeostasis (Figure 4E). Iron uptake principally proceeds through iron bound to transferrin mediated via the transferrin receptor or via direct uptake of Fe2+ facilitated by a variety of receptors including TRPC6 (Mwanjewe and Grover, 2004). We propose that upregulation of TRPC6 manifests in increased uptake of Fe2+, while downregulation of HFE (which competes with Tf), results in uptake of more ferric iron which can further be reduced into Fe2+. In contrast, export of heme-bound iron via ABCG2 or unbound Fe2+ through FPN can be reduced. Concordant with this model, we confirmed in several individual differentiation experiments a small but significant increase of intracellular iron within 5 weeks of neuronal differentiation in FTD3 neurons. Excessive amounts of intracellular Fe2+ are toxic to cells and trigger the production of ROS. Moreover, Fe2+ and hydrogen peroxide engage in the so-called Fenton reaction, producing ferric iron and highly reactive hydroxide, which damages DNA, proteins, and lipids in the cell (Altamura and Muckenthaler, 2009).
    Experimental Procedures
    Author Contributions
    Acknowledgments This work was supported by awards from: EU FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP) grant (STEMMAD, PIAPP-GA-2012-324451), Innovation Fund Denmark (BrainStem, 4108-00008B), Lundbeck Foundation (R151-2013-14439) (L.B.), Danish Research Council for Independent Research (DFF-1337-00128 and DFF-1335-00763) (Y.L.), China Scholarship Council (Y.Z.), and Ministry of Science, Technology and Innovation of Mexico (B.I.A.). We are grateful to the FTD3 family for their support of this work. Finally, we would like to thank Ms. Hanne Holm and Tina Christoffersen from the University of Copenhagen, Ms. Ulla Poulsen from Bioneer A/S, and Mr. Lingfei Ye from BGI-Shenzhen for expert technical assistance.
    Introduction Neurons communicate primarily by regulated secretion of signaling molecules via two secretory pathways, using synaptic vesicles (SVs) and using dense-core vesicles (DCVs). SVs contain neurotransmitters responsible for fast signaling (Kaeser and Regehr, 2014; Rizo and Sudhof, 2012; Sudhof and Rothman, 2009), whereas DCVs store neuromodulators such as neuropeptides and neurotrophins that regulate sirtuin inhibitors development, synaptogenesis, and synaptic plasticity (Huang and Reichardt, 2001; Park and Poo, 2013; van den Pol, 2012; Zaben and Gray, 2013). While SVs recycle locally in nerve terminals, DCVs are filled with cargo at the trans-Golgi network (TGN). After post-Golgi maturation (Kim et al., 2006), DCVs are transported by microtubule-linked motor proteins to specific fusion sites (de Wit et al., 2006; Maeder et al., 2014), where they secrete their cargo upon high-frequency stimulation (HFS) (Farina et al., 2015; Shimojo et al., 2015; van de Bospoort et al., 2012). Currently, insight into these regulated secretory pathways comes mostly from rodent neuronal cultures, invertebrates, or human immortalized cell lines, but validation of such insight in human, post-mitotic neurons is currently lacking, despite new opportunities to do so using human induced pluripotent stem cell (iPSC)-derived neurons. Human iPSC-derived neurons provide new tools to model human brain disorders, test therapeutic targets on a patient-own background, and conduct translational studies (Ichida and Kiskinis, 2015). Dysregulation of the regulated secretory pathways is evidently linked to many brain disorders, including post-traumatic stress disorder, cognitive impairment (Meyer-Lindenberg et al., 2011; Sah and Geracioti, 2013), schizophrenia, autism, or intellectual disability (Volk et al., 2015). Studies on regulated secretory pathways in human iPSC-derived neurons will be important to better understand the etiology of these disorders. Several recent studies have demonstrated that SV secretion is functional in human neurons, using postsynaptic recordings in synaptic networks of human neurons. However, surprisingly few studies (such as Chanda et al., 2014; Sun et al., 2016; Yi et al., 2016; Zhang et al., 2013) have reported evoked secretion, which is the basis for synaptic transmission, and most studies only report spontaneous fusion of SVs, of which the biological significance is unclear. For trafficking and secretion of DCV cargo, such as neuropeptides and neurotrophic factors, even fewer studies have been conducted in human neurons and these ones provide limited resolution of the secretion process (Hook et al., 2014; Merkle et al., 2015). Hence, the characterization of secretory pathways in human iPSC-derived neurons remains limited and it is unclear to what extent human neurons model mature secretory pathways in the brain, a prerequisite to investigate human brain disorders.