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Wolframin is a novel regulator of tau pathology and neurodegeneration

Chen, S; Acosta, D; Li, L; Liang, J; Chang, Y; Wang, C; Fitzgerald, J; ... Fu, H; + view all (2022) Wolframin is a novel regulator of tau pathology and neurodegeneration. Acta Neuropathologica , 143 pp. 547-569. 10.1007/s00401-022-02417-4. Green open access

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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.

Type: Article
Title: Wolframin is a novel regulator of tau pathology and neurodegeneration
Location: Germany
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00401-022-02417-4
Publisher version: https://doi.org/10.1007/s00401-022-02417-4
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Alzheimer’s disease, Autophagy-lysosome pathway, ER stress, Entorhinal cortex, Neurodegeneration, Neuronal vulnerability, Tau pathology, WFS1, Wolframin
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10147233
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