Understanding the molecular mechanism of adaptive thermotolerance in E coli

Abstract

Homocysteine (Hcy), a non protein sulphur containing amino acid, its elevated levels is long newlinebeen clinically related to several neurological disorders. Additionally increased concentration of newlineHcy has the potential to cause neurological cell death. Previous reports have highlighted various newlineobservations like ER stress, oxidative stress, mitochondrial dysfunction etc during newlineHyperhomocystemic conditions. However, none of these observations have given a detailed newlinemechanism of Hcy induced neurotoxicity. Using cultured neuronal cells and a newlinehyperhomocysteinemic Zebra fish model we show that Hcy causes neuronal apoptosis associated newlinewith mitochondrial dysfunction. We also document high ER-stress in hyperhomocysteinemic newlinecondition and show that this ER-stress is upstream to mitochondrial apoptosis. We confirm this newlineobservation by rescuing mitochondrial functionality and neuronal apoptosis by inhibition of ERstress. Our data suggest that this detrimental ER-mitochondria crosstalk is mainly dependent on newlineproteotoxicit y and is independent of ROS and Calcium signaling. As neurons mainly use newlineautophagy to maintain protein homeostasis, we check the effect of Hcy on autophagy. Our result newlineshow that Hcy causes suppression of basal neuronal autophagy leading to increased ubiqutinated newlineprotein aggregates and that in turn aggravate the ER-stress and consequent neuronal apoptosis. newlineWe confirm our findings by rescuing all these effects upon activation of autophagy through newlinegenetic and pharmacological manipulation. newlineIn conclusion our data suggest that downregulation of basal autophagy is the earliest event in newlinehyperhomocysteinemia which leads to increased proteotoxicity and concomitant ER-stress. This newlinesustained ER-stress finally causes mitochondrial dysfunction and neuronal apoptosis. newline118 newlineSignificance of the study: This study provides the exact sequence of molecular events taking newlineplace during Hcy-induced neurotoxicity.