Waldherr, S.M. et al. Nat. Commun. 10, 4443 (2019)

The endoplasmic reticulum unfolded protein response (UPRER) is a conserved, multistep means by which many different organisms maintain protein homeostasis. Such proteostasis naturally declines with age and is increasingly thought to be a contributing factor to neurodegenerative diseases that are marked by abnormal protein accumulations, such as Alzheimer’s disease (AD), Parkinson’s, and ALS.

Working with transgenic worms that express human tau, a protein associated with AD, researchers in Washington link components of the UPRER to pathology in a living organism. The team identified two genes directly involved in UPRER signaling pathways that, when knocked out, lead to increased tau accumulation and disrupted mobility in the worms. Overexpression of the master transcription factor involved, XBP-1, ameliorated the pathological protein burden, as did increasing expression of two genes that in turn have roles in activating XBP-1.