Uncovering the role of WFS1 deficiency in selective vulnerability in Alzheimer's disease - Project Summary/Abstract Selective neuronal and regional vulnerability to tau protein aggregation is found in many neurodegenerative diseases including Alzheimer’s disease (AD). Understanding the molecular origins of this selective vulnerability and mechanisms underlying tau degradation and clearance are therefore of fundamental importance to elucidate the pathogenesis of AD. Previous studies from our group and others have shown that excitatory (EX) neurons expressing wolframin (WFS1) in the entorhinal cortex (EC) layer-II are a major cell type preferentially vulnerable to tau pathology and cell death compared to other layers/regions in human AD and tau mouse models. WFS1 is an integral ER-membrane glycoprotein that regulates ER stress and autophagy, two processes that interconnect and are implicated in the clearance of pathological tau. It is not clear, however, how WFS1 promotes pathological tau clearance, why WFS1 level is reduced in AD, and why reduced WFS1 makes EX neurons in EC layer-II vulnerable to tau pathology and neurodegeneration. We have recently reported that knockout (KO) of WFS1 increases tau pathology and reduces the expression of a master regulator (i.e., Transcription Factor EB, TFEB) of the autophagy-lysosome pathway (ALP) in the EC of PS19 tau mice. Overexpression of WFS1 increases TFEB and reverses the inhibition of autophagy flux. 14-3-3 proteins bind to phospho-TFEB and inhibit its nuclear translocation and the activation of ALP. Our pilot results reveal that 14-3-3 proteins interact with WFS1, suggesting WFS1 may interact with 14-3-3 proteins and release its inhibition of TFEB nuclear translocation, resulting in ALP activation. Smad ubiquitination regulatory factor 1 (Smurf1), which degrades WFS1 protein, is increased in tangle-bearing neurons in human AD, indicating increased Smurf1 may reduce WFS1 and inhibit ALP induction. Pathological tau and Smurf1 have been found to induce cell death mainly via necroptosis and correlate well with memory loss in AD. We also find that WFS1 KO increases necroptosis (also found in tangle-bearing neurons in human AD) and reduces long-term potentiation in htau knock-in mice. In addition, single nucleus RNA-seq analysis shows WFS1-high EX neurons are intrinsically enriched with genes associated with tau protein homeostasis, which can tip the proteostasis towards tau aggregation under pathological conditions with reduced WFS1. Thus, we hypothesize that both intrinsic factors (e.g. WFS1- expressing cell properties) and extrinsic factors (e.g. epigenetics and environment)-triggered disruption in the Smurf1-WFS1-14-3-3-TFEB axis contribute to selective vulnerability of WFS1-expressing EX neurons in the EC in early AD. We aim to (1) define molecular signatures underlying selective vulnerability of WFS1-expressing EX neurons in the EC; (2) investigate why WFS1 level is reduced in EX neurons and why WFS1 deficiency induces cell death and cognitive deficits in AD; and (3) determine the mechanistic role of WFS1- 14-3-3-TFEB axis in tau pathology. The proposed studies will provide significant insights into the role of WFS1 in AD, the molecular mechanisms underlying selective vulnerability in early AD, and novel drug targets for AD.
