Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy

Abstract

Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer’s disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect—depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer’s disease and other tauopathies.

Decreased anterograde transport coupled with sustained retrograde transport contributes to reduced axonal mitochondrial density in tauopathy neurons

“…In the current study, we have provided more evidence to substantiate the role of altered motor-cargo interactions as a contributing factor to mitochondrial transport defects in P301L neurons. Consistent with the previous reports (Jeong et al, 2022), overexpression of P301L in mouse primary cortical neurons reduced anterograde movement of mitochondria, while having minimal effect on retrograde transport. Our data revealed that such defects are caused by reduced recruitment of kinesin motors to mitochondria in P301L cells.…”

“…As shown in Figures 1A,B, overexpression of wildtype tau did not affect either anterograde or retrograde transport of mitochondria. This is consistent with our previous work that control and wild-type tau expressing neurons display similar transport kinetics (Jeong et al, 2022). However, P301L tau selectively reduced anterograde mitochondrial transport but had minimal impact on retrograde transport in the same axon, ruling out the possibility of microtubule destabilization (Figure 1B).…”

“…Since damaged mitochondria are not transported efficiently in the anterograde direction (Miller and Sheetz, 2004;Quintanilla et al, 2020), our model also predicted that the number of defective mitochondria appears to increase with the phosphorylation status of tau (Jeong et al, 2022). This is also similar to an increase in the faulty mitochondria in both axons and soma of P301L neurons (Jeong et al, 2022).…”

“…This is also similar to an increase in the faulty mitochondria in both axons and soma of P301L neurons (Jeong et al, 2022). The quantity of defective mitochondria was proportional to reduced kinesin activity and mitophagy induced by tau phosphorylation (Jeong et al, 2022). So, we considered mitophagy correlates with tauopathy as the function of τ k f and estimated it as an inverse function of the effect of tau phosphorylation on kinesin activity.…”

A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model

“…Mitophagy is a critical mechanism in mitochondrial quality control that targets damaged mitochondria for autophagy. However, little is known about the relationship between mitophagy and pathologies in AD and other tauopathies (Jeong et al, 2022). The serine/threonine‐protein kinase (PINK1) and the E3 ubiquitin‐protein ligase (PARKIN) were recently involved in eliminating defective mitochondria by mitophagy (Cai & Jeong, 2020; Pradeepkiran et al, 2020; Sun et al, 2012).…”