Glutamatergic nervous system degeneration in a C. elegans TauA152T tauopathy model involves pathways of excitotoxicity and Ca2+ dysregulation

Abstract

Mutations in the gene encoding Tau (MAPT-microtubule-associated protein tau) cause a group of neurodegenerative diseases called tauopathies. A recently identified Tau variant, p.A152T, has been reported as a risk factor for frontotemporal dementia-related disorders and Alzheimer disease. However, the mechanism for the pathologies still remain poorly understood. Transgenic Caenorhabditis elegans expressing mutant 2N4R-TauA152T (TauAT) panneuronally show locomotor defects, neurodegeneration and accelerated aging. Here we report that, in TauAT animals, the glutamatergic nervous system is at a high risk of progressive neuronal loss. We present genetic data that this loss occurs predominantly through necrosis. The neuronal loss is caused by several determinants, such as altered adenylyl cyclase (type AC9) pathway, prevalence of excitotoxicity-like conditions, aging-related factors and finally dyshomeostasis of intracellular calcium (Ca2+). The study provides novel insights into the mechanisms involved in selective loss of glutamatergic neurons in a TauAT tauopathy model which could point to new therapeutic targets.