Alteration of mitochondrial homeostasis is an early event in a C. elegans model of human tauopathy

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  • Konstantinos Palikaras
  • Kavya Achanta
  • Seoyun Choi
  • Mansour Akbari
  • Bohr, Vilhelm

Tauopathies are a group of progressive neurodegenerative disorders characterized by the presence of insoluble intracellular tau filaments in the brain. Evidence suggests that there is a tight connection between mitochondrial dysfunction and tauopathies, including Alzheimer’s disease. However, whether mitochondrial dysfunction occurs prior to the detection of tau aggregates in tauopathies remains elusive. Here, we utilized transgenic nematodes expressing the full length of wild type tau in neuronal cells and monitored mitochondrial morphology alterations over time. Although tau-expressing nematodes did not accumulate detectable levels of tau aggregates during larval stages, they displayed increased mitochondrial damage and locomotion defects compared to the control worms. Chelating calcium restored mitochondrial activity and improved motility in the tau-expressing larvae suggesting a link between mitochondrial damage, calcium homeostasis and neuronal impairment in these animals. Our findings suggest that defective mitochondrial function is an early pathogenic event of tauopathies, taking place before tau aggregation and undermining neuronal homeostasis and organismal fitness. Understanding the molecular mechanisms causing mitochondrial dysfunction early in tauopathy will be of significant clinical and therapeutic value and merits further investigation.

OriginalsprogEngelsk
TidsskriftAging
Vol/bind13
Udgave nummer21
Sider (fra-til)23876-23894
Antal sider19
ISSN1945-4589
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
Supported by the Olav Thon Foundation, CESA and the intramural Program at the National Institute on Aging, NIH, USA.

Funding Information:
Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources of the National Institutes of Health. We thank E.M. Mandelkow for PIR3 transgenic nematodes.

Publisher Copyright:
© 2021. Palikaras et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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