The Gαq/phospholipase Cβ signaling system represses tau aggregation

• Published in: Cellular signalling Vol. 71; p. 109620
• Main Authors: Garwain, Osama, Yerramilli, V. Siddartha, Romero, Kate, Scarlata, Suzanne
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.07.2020
• Subjects: Animals; Calcium - metabolism; Calcium signaling; Cyclin-Dependent Kinases - metabolism; Fluorescence imaging; G2 Phase; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Mitosis; Mitotic hypothesis; PC12 Cells; Phospholipase C beta - metabolism; Phospholipase Cbeta; Protein Aggregates; Protein Binding; Rats; Signal Transduction; Tau aggregation; tau Proteins - metabolism; Calcium signaling; Phospholipase Cbeta; Fluorescence imaging; Mitotic hypothesis; Tau aggregation
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2020.109620

Alzheimer's disease is typified by calcium dysfunction and neurofibrillary tangles of tau aggregates along with mitotic proteins. Using PC12 cells as a model system, we determined whether the Gαq/PLCβ/ calcium signaling pathway impacts the manifestation of Alzheimer's disease. Down-regulating PLCβ significantly increases tau protein expression and causes a large increase in tau aggregation. Stimulating Gαq to activate PLCβ results in a modest reduction in tau aggregation while inhibiting PLCβ activity results in a modest enhancement of tau aggregation. These results suggest that PLCβ may effect tau aggregation by an additional mechanism that is independent of its ability to transduce calcium signals. To this end, we found that a cytosolic population of PLCβ binds to a mitotic protein found in neurofibrillary tangles, CDK18, which promotes tau phosphorylation and aggregation. Taken together, our studies show that the loss of PLCβ1 can promote Alzheimer's disease by a combination of its catalytic activity and its interaction with mitotic proteins thus offering an orthogonal method to control tau aggregation. [Display omitted] •Alzheimer's disease is typified by calcium dysfunction and tau aggregates.•Gαq/PLCβ signaling pathway generate calcium signals.•Down-regulating PLCβ significantly increases tau protein expression and aggregation.•Inhibiting PLCβ activity results in a modest enhancement of tau aggregation.•PLCβ binds to CDK18 promoting tau phosphorylation and aggregation.