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Title: Reticulon 1C induces Disruption of Ca2+ Signaling and Alteration in Mitochondrial Dynamics in vitro and Neurodegeneration in vivo
Authors: Al Mehdawy, Bisan
Supervisors: Nisticò, Robert
Willis, Anne
Award date: 1-Feb-2012
Presented at: University of Leicester
Abstract: Endoplasmic reticulum (ER) is a key organelle fundamental for the maintenance of cellular homeostasis and for determination of cell fate under stress conditions. Among the proteins known to regulate ER structure and function is reticulon-1C (RTN-1C), a member of the reticulon family proteins localized primarily on the ER membrane. Previous studies suggested that RTN-1C is able to trigger ER stress-induced cell death, although the exact mechanism still remains unclear. Based on these findings, here I have further investigated the impact of RTN-1C overexpression on Ca2+ signaling and mitochondrial dynamics in human neuroblastoma cell line. When transiently overexpressed, RTN-1C is linked to disruption of intracellular Ca2+ homeostasis, Ca2+-dependent autophagy and mitochondrial elongation. Conversely, RTN-1C mediated prolonged ER-stress was able to induce over time mitochondrial fragmentation and cell death. Importantly, neuronal loss was rescued by the novel JNK inhibitor D-JNKI1, supporting a crucial role for this pathway in RTN-1C induced apoptosis. These in vitro data were then supported by in vivo evidence obtained on a transgenic mouse overexpressing RTN-1C. This model displayed alterations in the expression profile of specific genes and neurodegenerative features in the cerebral cortex. Overall, this work defines a role for RTN-1C as a potential molecular target for use in therapy and as a specific marker for neurological/neurodegenerative diseases.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author, 2012
Description: Figures are available as a seperate file.
Appears in Collections:Theses, MRC Toxicology Unit
Leicester Theses

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