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Title: Regulation of cellular energy metabolism : implications for Parkinson's disease
Author: Weinert, Maria
ISNI:       0000 0004 7427 7336
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Mutations in DJ-1 (PARK7) gene cause recessive, early-onset Parkinson‘s disease. DJ-1 is a neuroprotective oncogene that translocates from the cytoplasm to mitochondria under cellular stress conditions. The neuroprotective role of DJ-1 against reactive oxygen species has been extensively studied but its normal, physiological function is not fully understood. 14-3-3beta is a conserved protein of the 14-3-3 family of chaperones that are implicated in regulation of metabolism in part through regulation of subcellular localisation of their targets. We found that 14-3-3beta interacts with DJ-1 in a phosphorylation-dependent manner. Furthermore, 14-3-3beta inhibits the translocation of DJ-1 to mitochondria under normal cell physiological conditions. The knockdown of 14-3-3beta leads to increased mitochondrial membrane potential, likely through the enhanced mitochondrial translocation of DJ-1. 14-3-3beta knockdown cells show increased proliferation rates under normoxia and hypoxia and are more sensitive to chemical inhibition of mitochondrial ATP production compared to control cell lines. These results suggest that the interaction between DJ-1 and 14-3-3beta plays a role in cellular metabolic balance by influencing the cellular preference for glycolysis or oxidative phosphorylation as the two main modes of ATP production. We also postulate that the neuronal metabolic balance, regulated by the interaction between DJ-1 and 14-3-3beta, is required for cellular adaptation to environmental stress or synaptic activity.
Supervisor: Alavian, Kambiz ; Dexter, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral