| dc.description.abstract | Divalent metal ions are participated in many physiological mechanisms. Current literature has shown the cause of neurodegenerative diseases is correlated with disrupted metal homeostasis. In clinical study, it was found that the concentration of metal ions in cerebrospinal fluid (CSF) in amyotrophic lateral sclerosis (ALS) patients is higher. In addition, divalent metal ions induce pathological TDP-43 formation in vivo. Though it is shown divalent metal ions enhance the transmission of pathological proteins, however, there is no direct evidence showing TDP-43 following the similar scenario. Since the cell-to-cell transmission of pathological TDP-43 is considered as a defensive mechanism, we would like to investigate whether if the stimulation of divalent metal ion enhanced the formation of pathological TDP-43 fragments (C-TDP-43) and transmitted C-TDP-43 into recipient cells. In this study, we found three divalent metal ions (Zn2+, Mg2+, Pb2+) cause TDP-43 mislocalization in neuronal cells. By characterizing the vesicles in cultured medium, we found that pathological TDP-43 fragments were included in exosomes. Furthermore, we found Zn2+ and Pb2+ induced more exosomes by nanoparticle tracking analysis. With the help of transmission electron microscopy, we also notice Pb2+ induced smaller exosomes than all the other cases. In addition, metal ion-induced exosomes not only cause TDP-43 mislocalization in recipient cells, but also decrease TDP-43 fluidity in nucleus. Even more, these exosomes induced inflammation response in microglia cells. Finally, we have shown that the stimulation Mg2+ and Pb2+ enhanced the content of C-TDP-43 in exosomes, while Zn2+ and Pb2+ enhanced the compactness of C-TDP-43 inside exosomes. Conclusively, we demonstrated three divalent metal ions (Zn2+, Mg2+, Pb2+) were able to cause TDP-43 mislocalization and induce exosome secretion. Within these cases, Pb2+ particularly induced significant C-TDP-43 fragments accumulation and more cell-to-cell transmission. Therefore, Pb2+ could play a dominate role on cell-to-cell transmission of pathological TDP-43 fragments. | en_US |