Neurotherapeutic implications of sense and respond strategies generated by astrocytes and astrocytic tumours to combat pH mechanical stress.

Neuropathology and Applied Neurobiology   23 November 2021| 10.1111/nan.12774 

Sebastian John, Gayathri K.G, Aswani P. Krishna, Rashmi Mishra* (*Corresponding author)

ABSTRACT

Astrocytes adapt to acute acid stress. Intriguingly, cancer cells with astrocytic differentiation thrive even better in an acidic microenvironment. How changes in extracellular pH (pHe) are sensed and measured by the cell surface assemblies that first intercept the acid stress, and how this information is relayed downstream for an appropriate survival response remains largely uncharacterized. In vitrocell-based studies were combined with anin vivoanimal model to delineate the machinery involved in pH microenvironment sensing and generation of mechanoadaptive responses in normal and neoplastic astrocytes. The data was further validated on patient samples from acidosis driven ischaemia and astrocytic tumour tissues. We demonstrate that low pHe is perceived and interpreted by cells as mechanical stress. GM3 acts as a lipid-based pH sensor, and in low pHe, its highly protonated state generates plasma membrane deformation stress which activates the IRE1-sXBP1-SREBP2-ACSS2 response axis for cholesterol biosynthesis and surface trafficking. Enhanced surface cholesterol provides mechanical tenacity and prevents acid-mediated membrane hydrolysis, which would otherwise result in cell leakage and death. In summary, activating these lipids or the associated downstream machinery in acidosis-related neurodegeneration may prevent disease progression, while specifically suppressing this key mechanical 'sense-respond' axis should effectively target astrocytic tumour growth.

Contact

Rajiv Gandhi Centre for Biotechnology (RGCB),
Thycaud Post, Poojappura,
Thiruvananthapuram - 695 014, Kerala, India
+91-471-2529400 | 2347975 | 2348753
+91-471-2348096
webmaster@rgcb.res.in

My Gov www.mygov.in Prime Ministers National Relife Fund India Gov www.india.gov.in Make In India www.makeinindia.gov.in Make In India www.iredibleindia.org Data gov in www.data.gov.in www.pib.gov.in

Last Updated on: January 24, 2022
CERT-In Certified Website