4.6 Article

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

Journal

AGING-US
Volume 13, Issue 21, Pages 23876-23894

Publisher

IMPACT JOURNALS LLC

Keywords

aging; Alzheimer's disease; C. elegans; energy metabolism; mitochondria; tau; tauopathy

Funding

  1. Olav Thon Foundation
  2. CESA
  3. intramural Program at the National Institute on Aging, NIH, USA

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Evidence suggests that mitochondrial dysfunction precedes tau aggregation in tauopathies, impacting neuronal homeostasis and mobility in animals. Understanding the early molecular mechanisms of mitochondrial dysfunction in tauopathy holds significant clinical and therapeutic value.
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.

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