Broad activation of the PRKN pathway triggers synaptic failure by disrupting synaptic mitochondrial supply in early tauopathy

Mitochondrial defects are a hallmark of Alzheimer disease (AD), with pathologically phosphorylated MAPT/tau (phospho-MAPT/tau) reported to induce mitochondrial damage. Mitophagy constitutes a key pathway of mitochondrial quality control by which damaged mitochondria are sequestered within autophagosomes for lysosomal degradation. However, the mechanistic understanding of mitophagy and its association with pathologies under tauopathy conditions remains very limited. Here, we reveal that mitochondrial stress under phospho-MAPT/tau-mediated challenges broadly activates PRKN-mediated mitophagy which induces an unexpected effect - depletion of mitochondria from synaptic terminals, a characteristic feature in early tauopathy. PRKN activation accelerates RHOT1 turnover and consequently halts RHOT1-mediated mitochondrial anterograde movement, which disrupts mitochondrial supply to tauopathy synapses and thereby impairs synaptic function. Strikingly, increasing RHOT1 levels prevents synapse loss and reverses cognitive impairment in tauopathy mice by restoring synaptic mitochondrial populations. Thus, our study uncovers an important early mechanism underlying tauopathy-linked synaptic failure and opens a new avenue for specifically targeting early synaptic dysfunction in tauopathies, including AD.

Automated summary

Mitochondrial defects and phosphorylated MAPT/tau induce mitochondrial damage and activate mitophagy, which depletes mitochondria from synaptic terminals and impairs synaptic function. Increasing RHOT1 levels can reverse cognitive impairment and prevent synapse loss in tauopathy mice.