Tau pathology as a cause and consequence of the UPR.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Abisambra et al. The endoplasmic reticulum (ER) is a site of protein processing and quality control in the cell, replete with mechanisms for recognizing misfolded proteins and resolving proteotoxic stress. These control mechanisms are collectively known as the ER unfolded protein response (UPR; reviewed by Schröder and Kaufman, 2005). UPR signal transduction pathways are orchestrated by the coordinated actions of three key transmembrane proteins: inositol-requiring enzyme 1␣ (IRE1␣), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK). Together with the ER chaperone BiP, which helps ensure proper protein folding, these factors mediate a rapid and multifaceted response to the accumulation of unfolded proteins in the ER lu-men. When activated, the UPR initially induces selective suppression of protein translation, and elevates the expression of chaperones and antioxidant proteins. Additionally , the UPR promotes the stepwise removal of persistently misfolded proteins through ER-associated degradation (ERAD) and the ubiquitin proteasome system (Schröder and Kaufman, 2005). However, chronic activation of the UPR elicits a transition from these generalized prosurvival responses toward one of cell death via apoptosis. Neurological disorders such as Parkinson's disease, Hun-tington's disease, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) feature both UPR activation and ERAD dysfunction (Roussel et al., 2013). In AD and other neurodegenerative diseases collectively called tauopathies, the microtubule-associated protein tau becomeshyper-phosphorylatedandformsin-soluble intracellular aggregates associated with disease progression (reviewed by Spill-antini and Goedert, 2013). Although a tremendous amount of research has investigated the role of tau in neurodegeneration, the underlying mechanisms of tau toxicity remain elusive. In their recent article in The Journal of Neuroscience, Abisambra et al. (2013) offer insight into the nature of tau toxicity by revealing that aberrant soluble tau species impair ERAD and activate the UPR. The authors first demonstrate that the appearance of phosphorylated PERK (pPERK), an early marker of incipient ER stress and UPR activation , accompanies the accumulation of soluble tau in rTg4510 mice. These animals conditionally express P301L mutant human 4R0N tau, which has an increased tendency to aggregate and is associated with the heri-table tauopathy, frontotemporal dementia (Alonso Adel et al., 2004; Santacruz et …