Biology subjects

Karuppagounder, S. S.

Publications and source records attributed to Karuppagounder, S. S..

2 recordsLinked to original sources

bioRxiv2022

Enhanced mTORC1 signaling and Protein Synthesis in Parkinson Disease Pathogenesis

Pathologic -syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD. AbstractPathological -synuclein (-syn) plays an important role in the pathogenesis of -synucleinopathies such as Parkinsons disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic -syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the -syn preformed fibril (PFF) and Drosophila -syn transgenic models of pathologic -syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic -syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.

neuroscience↗

bioRxiv2020

HIF1α stability in hypoxia is not oxidant-initiated but can be tuned by redox regulation of the proteasome

Hypoxic adaptation mediated by HIF transcription factors has been shown to require mitochondria. Current models suggest that mitochondria regulate oxygen sensor (HIF prolyl hydroxylase) activity and HIF1 stability during hypoxia by either increasing mitochondrial peroxide as a second messenger or by serving as oxygen consumers that enhance the kinetics of cytoplasmic oxygen reduction. Here, we address the role of mitochondrial peroxide specifically in regulating HIF1 stability. We use state-of-the-art tools to evaluate the role of peroxide and other reactive oxygen species (ROS) in regulating HIF1 stability. We show that antioxidant enzymes are not homeostatically induced nor are peroxide levels increased in hypoxia. Forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1 protein stability. Reduction of lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD failed to influence HIF1 protein stability. These data showed that mitochondrial, cytosolic and lipid ROS are dispensable for HIF1 stability and should affirm therapeutic efforts to activate the HIF pathway in disease states by HIF prolyl hydroxylase inhibition.

cell biology↗