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Wolframin is a novel regulator of tau pathology and neurodegeneration
Journal article   Peer reviewed

Wolframin is a novel regulator of tau pathology and neurodegeneration

S. Chen, D. Acosta, L. Li, J. Liang, Y. Chang, C. Wang, J. Fitzgerald, C. Morrison, C.N. Goulbourne, Y. Nakano, …
Acta Neuropathologica, Vol.143(5), pp.547-569
2022
DOI: https://doi.org/10.1007/s00401-022-02417-4
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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.

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Collaboration types
Domestic collaboration
International collaboration
Citation topics
1 Clinical & Life Sciences
1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis
1.25.1406 Unfolded Protein Response
Web Of Science research areas
Clinical Neurology
Neurosciences
Pathology
ESI research areas
Neuroscience & Behavior
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