Constitutive XBP-1s-Mediated Activation of the Endoplasmic Reticulum Unfolded Protein Response Protects against Pathological Tau
This week we profile a recent publication in Nature Communications
from the laboratory of Dr. Brian Kraemer (pictured, left) at UW.
Can you provide a brief overview of your lab’s current research focus?
Overall, our research group investigates the molecular causes of neurodegeneration in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and related disorders of the nervous system. Our lab utilizes C. elegans, human cell culture, and mouse models for the tau pathology seen in AD and for the TDP-43 pathology seen in ALS in order to investigate disease mechanisms.
What is the significance of the findings in this publication?
The lack of disease-modifying therapeutics for age-related neurodegenerative diseases has highlighted the necessity of understanding underlying pathological mechanisms. Here, we demonstrate a novel tau protein detoxification pathway in neurons using a transgenic C. elegans model of human tau pathology. Activation of the protein homeostasis mechanism in the endoplasmic reticulum compartment known as the unfolded protein response (UPRER) promotes clearance of pathological tau in the cytoplasmic compartment, leading to reduction of behavioral abnormalities and subsequent neuronal survival in C. elegans. This demonstrates how global neuronal protein homeostasis can act a critical mediator of toxic protein accumulation during aging.
What are the next steps for this research?
Future translational studies will need to address whether UPRER activation can protect against pathological tau in the mammalian brain. Given the importance of the two transcriptional branches of the UPRER in tau pathology, our next step will be to identify xbp-1s target genes driving tau protein homeostasis in C. elegans, which could help inform more specific neuroprotective strategies in mammals.