Browsing Theses and Dissertations, Electronic (ETDs) by Author "Abalde-Atristain, Leire"
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ItemMOLECULAR MECHANISMS UNDERLYING THE NEUROPROTECTIVE EFFECTS OF AAA ATPase THORASE(Johns Hopkins University, 2019-05-20) Abalde-Atristain, Leire; Wong, Philip C; Worley, Paul F; Baraban, Jay M; Dawson, Valina L; Dawson, Ted MDiseases that affect the nervous system represent a great burden to society. Given the diverse etiology, designing neuroprotective strategies would provide a common therapeutic alternative for the prevention and treatment of these neurological conditions. In an attempt to understand the intrinsic mechanisms the brain possesses to maintain homeostasis and promote cell survival, our laboratory had previously discovered the AAA+ ATPase, Thorase. Using energy from ATP hydrolysis, Thorase regulates neuronal excitability through the internalization of AMPA receptors, and it maintains mitochondrial and peroxisomal integrity by extracting mislocalized proteins out of these organelles. Since the family of AAA+ ATPases is known for associating with diverse cellular functions, and the clinical manifestation of emerging pathogenic Thorase variants is miscellaneous, elucidating additional Thorase functions would help us better understand its neuroprotective effects and harness its therapeutic potential. In this study, we uncovered a novel role for Thorase in regulating mechanistic target of rapamycin complex 1 (mTORC1) signaling. We have shown that Thorase directly binds mTOR, thereby orchestrating the disassembly of the mTORC1. In the absence of Thorase, mTORC1 signaling and downstream processes were upregulated. Importantly, the mTORC1 hyperactivity observed in the absence of Thorase could be alleviated through the FDA-approved mTOR inhibitor rapamycin. Moreover, rapamycin substantially prolonged survival of mice lacking Thorase, which typically die of severe seizures shortly after birth. Collectively, these findings revealed a key role for Thorase as negative regulator of the mTORC1 signaling pathway that acts through the disassembly of the mTORC1, thereby suggesting Thorase neuroprotective effects rely on maintaining neurons in a bioenergetically favorable state.