Neuropathology in tauopathies stem from depolarization-induced alterations in the planar distribution of phosphoinositides

Tau蛋白缠结是阿尔茨海默病相关痴呆（adrd）的共同特征，并诱导一系列

Tau tangles are common features of Alzheimer’s disease related dementias (ADRDs) and induce a range of pathological perturbations in neurons including hyperexcitability and Ca2+ dyshomeostasis. In this application, we use Drosophila to demonstrate that progressive neurotoxicity elicited by Tau or hexanucleotide repeat expansion of C9ORF72 involves elevated production of the second messenger, inositol trisphosphate (IP3), and activation of IP3 receptor (IP3R)-mediated ER Ca2+ release. Thus, premature lethality stemming from expression of ADRD-causing transgenes was almost fully suppressed by attenuation of IP3 production or knockdown IP3Rs. Although IP3Rs have been previously implicated in neurodegeneration, we have uncovered a novel mechanism underlying channel hyperactivation. We show expression of ADRD-causing transgenes leads to loss of neuronal membrane potential, and that the resulting depolarization is what increases IP3R activity. Our preliminary findings are consistent with the notion that depolarization increases association of an enzyme responsible for IP3 production, phospholipase Cb (PLCb), with its phosphoinositide substrate, PIP2. Greater PLCb–PIP2 interactions in depolarized cells lead to elevated IP3 production upon stimulation of PLCb-coupled receptors. In Aim 1, we will test the aforementioned hypothesis in fly and mouse neurons expressing mutant tau. We also ask how ADRD neurons lose their ability to maintain membrane potential. Based on electrophysiological recordings and analyses of RNA-seq datasets, we hypothesize that chronic depolarization stems from diminished abundance of neuronal K+ leak channels that are needed for establishing normal resting membrane potential. In Aim 2, we seek to determine how depolarization potentiates PLCb–IP3R signaling. Our findings suggest that membrane potential dependent regulation of PLCb—PIP2 association and hydrolysis depend on the lipids’ acyl side chains. Taken in conjunction with our findings that depolarization promotes IP3 production, we hypothesize that PLCb activity depends on PIP2 side chain identity, and increases in depolarized cells due to the preferential hydrolysis of species with longer and more unsaturated side chains. Successful completion of the proposed studies would demonstrate that IP3R hyperactivation in ADRD neurons is agnostic to the causal mutations — an insight that speaks to the wide applicability of our findings. We also hope to develop strategies that can be leveraged to selectively change the population of PIP2 species at the plasma membrane in order to correct pathological Ca2+ dyshomeostasis that occurs in ADRD.