Wolframin is a novel regulator of tau pathology and neurodegeneration

Shuo Chen, Diana Acosta, Liangping Li, Jiawen Liang, Yuzhou Chang, Cankun Wang, Julie Fitzgerald, Cody Morrison, Chris N. Goulbourne, Yoshi Nakano, Nancy C.Hernandez Villegas, Lalitha Venkataraman, Cris Brown, Geidy E. Serrano, Erica Bell, Trina Wemlinger, Min Wu, Olga N. Kokiko-Cochran, Phillip Popovich, Xena E. FlowersLawrence S. Honig, Jean Paul Vonsattel, Douglas W. Scharre, Thomas G. Beach, Qin Ma, Jeff Kuret, Sulev Kõks, Fumihiko Urano, Karen E. Duff, Hongjun Fu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer’s disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.

Original languageEnglish
Pages (from-to)547-569
Number of pages23
JournalActa Neuropathologica
Volume143
Issue number5
DOIs
StatePublished - May 2022

Keywords

  • Alzheimer’s disease
  • Autophagy-lysosome pathway
  • Entorhinal cortex
  • ER stress
  • Neurodegeneration
  • Neuronal vulnerability
  • Tau pathology
  • WFS1
  • Wolframin

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