Doctor of Philosophy (PhD)
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Lead neurotoxicity, cadmium neurotoxicity, neuronal calcium sensor, DREAM, lithium neuroprotection, presenelin, potassium channel, Alzheimer's disease
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Downstream regulatory antagonist modulator (DREAM) is 29 kDa neuronal calcium sensor (NCS) protein which is expressed in the hippocampus of the brain. DREAM is a multifunctional protein which is involved in a wide spectrum of biological processes, including regulation of potassium current in brain, modulation of pain, presenilin-1 processing, regulation of memory and learning. Exposure to toxic metals such as Pb2+ and Cd2+ have been associated with different types of neurodegenerative diseases. However, how these toxic metals induce neurotoxicity remains an active area of research. In this study, utilizing a combination of spectroscopic and calorimetric techniques, we demonstrated binding of these toxic metals to DREAM. We showed that Pb2+ and Cd2+ bind to EF-hands in DREAM and binding of these toxic metals alters DREAM secondary and tertiary structure. Pb2+ and Cd2+ association to DREAM also modulates DREAM interactions with FITC-labeled peptides that mimic binding sites of DREAM effector proteins, presenilin 1 and Kv channel in a similar way as Ca2+ binding. Considering the high sequence homology between DREAM and other NCS proteins, Pb2+ and Cd2+could bind to other NCS proteins and interactions of Pb2+ and Cd2+ to with NCS proteins could provide novel insight into the molecular mechanism of Pb2+ and Cd2+-induced neurotoxicity. Li+ has been used for the treatment of mental disorders for more than six decades. Increasing evidences from in vivo and in vitro studies have implicated that Li+ is a drug candidate for the treatment of neurogenerative diseases. However, the molecular mechanism through which Li+ exerts its therapeutic action has not elucidated yet. Here we investigated whether Li+ directly binds to DREAM and impact its structural and functional properties. We demonstrated that Li+ binding triggers structural rearrangement of DREAM and enhances DREAM interactions with site-1 and site-2 of the voltage-gated potassium channel. Results from this study suggest that DREAM and probably other NCS proteins are molecular targets of Li+ and binding of Li+ to DREAM could provide a novel insight into the molecular mechanism of Li+ therapeutic action.
Previously Published In
1. Azam, Samiol; Gessica St Louis; Miksovska, Jaroslava; (2019) Cadmium association to DREAM promotes DREAM interactions with intracellular partners in a similar manner as its physiological ligand, calcium. Metallomics; DOI: 10.1039/C9MT00059C.
2. Azam, Samiol; Miksovska, Jaroslava; (2019) Pb2+ binds to DREAM and modulates its interactions with binding partners: A link between neuronal calcium sensors and Pb2+ neurotoxicity. ACS Chemical Neuroscience; 10 (3), 1263–1272.
Azam, Samiol, "Consequences of Non-physiological Ligands Binding to DREAM on Its Secondary and Tertiary Structures and Interactions with Intracellular Partners." (2019). FIU Electronic Theses and Dissertations. 4325.
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