Increased G3BP2-Tau interaction in tauopathies is a natural defense against Tau aggregation.

Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple tauopathies, and it is independent of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we found that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in tauopathies.

Neuro-immune-metabolism: The tripod system of homeostasis.

Homeostatic regulation of cellular and molecular processes is essential for the efficient physiological functioning of body organs. It requires an intricate balance of several networks throughout the body, most notable being the nervous, immune and metabolic systems. Several studies have reported the interactions between neuro-immune, immune-metabolic and neuro-metabolic pathways. Current review aims to integrate the information and show that neuro, immune and metabolic systems form the triumvirate of homeostasis. It focuses on the cellular and molecular interactions occurring in the extremities and intestine, which are innervated by the peripheral nervous system and for the intestine in particular the enteric nervous system. While the interdependence of neuro-immune-metabolic pathways provides a fallback mechanism in case of disruption of homeostasis, in chronic pathologies of continued disequilibrium, the collapse of one system spreads to the other interacting networks as well. Current review illustrates this domino-effect using diabetes as the main example. Together, this review attempts to provide a holistic picture of the integrated network of neuro-immune-metabolism and attempts to broaden the outlook when devising a scientific study or a treatment strategy.