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Dysregulation of a novel autophagosome-mitochondria contact contributes to autophagy dysfunction and neurodegeneration in tauopathy
Problems in a new connection between cell cleanup and energy parts may contribute to cell recycling failure and brain damage in tau-related diseases
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Abstract
Autophagosome/mitochondria contact exhibits hyper-tethering in tauopathy neurons, leading to impaired cargo transport.
- Mitochondria and autophagic vacuoles communicate through specialized contacts that are disrupted in tauopathy.
- Hyper-tethering of these contacts is linked to a faster breakdown of TBC1D15, a key protein involved in their regulation.
- This breakdown is driven by increased activity of AMP-activated protein kinase (AMPK) due to mitochondrial energy deficits.
- Restoring TBC1D15 levels or inhibiting AMPK activity can normalize the contact between autophagosomes and mitochondria.
- Enhancing TBC1D15 levels improves the clearance of autophagic cargo and reduces tau accumulation in neurons.
- In tauopathy mice, increased TBC1D15 expression leads to better autophagic processes and less neurodegeneration.
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