Rlip76 in ageing and Alzheimer’s disease: Focus on oxidative stress and mitochondrial mechanisms

Abstract

RLIP76 (Rlip), a stress-responsive protein, plays a multifaceted role in cellular function. This protein acts primarily as a glutathione-electrophile conjugate (GS-E) transporter, crucial for detoxifying hazardous compounds and converting them into mercapturic acids. RLIP76 also modulates cytoskeletal motility and membrane plasticity through its role in the Ral-signaling pathway, interacting with RalA and RalB, key small GTPases involved in growth and metastasis. Beyond its ATP-dependent transport functions in various tissues, RLIP76 also demonstrates GTPase Activating Protein (GAP) activity towards Rac1 and Cdc42, with a preference for Ral-GTP over Ral-GDP. Its functions span critical physiological processes including membrane dynamics, oxidative stress response, and mitochondrial dynamics. The protein’s widespread expression and evolutionary conservation underscore its significance. Our lab discovered that Rlip interacts with Alzheimer's disease (AD) proteins, amyloid beta and phosphorylated and induce oxidative stress, mitochondrial dysfnction and synaptic damage in AD. Our in vitro studies revealed that overexpression of Rlip reduces mitochondrial abnormalities. Further, our in vivo studies (Rlip+/- mice) revealed that a partial reduction of Rlip in mice (Rlip+/−), leads to mitochondrial abnormalities, elevated oxidative stress, and cognitive deficits resembling late-onset AD, emphasizing the protein's crucial role in neuronal health and disease. Finally, we discuss the experimental cross-breedings of overexpression of mice Rlip ^TG/TG or Rlip + /- mice with Alzheimer’s disease models – earlyonset 5XFAD, late-onset APPKI and Tau transgenic mice, providing new insights into RLIP76’s role in AD progression and development. This review summarizes RLIP76’s structure, function, and cellular pathways, highlighting its implications in AD and its potential as a therapeutic target.