Efficient protein folding and prevention of abnormal aggregation in neurons relies on the protein homeostasis network. Cellular stress can increase misfolded proteins in the endoplasmic reticulum (ER), which activates the ER unfolded protein response (UPRER) to restore homeostasis. Although it is well-characterized in non-neuronal cells, current studies have revealed a key role for the UPRER in normal neuronal function during aging and neurodegenerative diseases. Neurodegenerative tauopathies are a group of age-related disorders classified by accumulation of hyperphosphorylated and aggregated tau protein in the cytoplasm. Recent work indicates the UPRER transcription factor XBP-1s might play a critical role in tau pathology. We previously generated a transgenic C. elegans tauopathy model. This model recapitulates hallmarks of pathology, such as neuronal loss and accumulation of abnormal tau species. Our results show that loss of
xbp-1 exacerbates tau-related phenotypes, including accumulation of abnormal tau protein and uncoordinated movement. Conversely, we found transgenic expression of constitutively active
xbp-1s ameliorates pathological tau-induced phenotypes, including uncoordinated movement, motor neuron loss, and abnormal tau protein accumulation. The UPRER is composed of three branches which can initiate independent and overlapping stress response pathways. To understand which UPRER stress sensor branches participate in tauopathy, we also investigated loss of
atf-6 and
pek-1. Our analysis suggests neither
atf-6 nor
pek-1 loss of function mutations modify tau toxicity. However, the ATF-6 branch is necessary for
xbp-1s-mediated amelioration of pathological tau-induced movement defects and abnormal tau protein accumulation. Aging is the greatest risk factor for developing neurodegenerative diseases. Interestingly, others have demonstrated
xbp-1s activation can also extend lifespan in C. elegans via
xbp-1-mediated neuronal signaling events (Taylor and Dillin, 2013). While the mechanistic nature of
xbp-1s effects on aging have yet to be dissected, we hypothesize the same
xbp-1s regulatory target genes mediate both lifespan extension and suppression of tauopathy. Because tau is a cytoplasmic protein, we propose target genes of
xbp-1s include those involved in protein homeostasis mechanisms outside of the ER, such as ER-associated degradation.