Mao-B elevation decreases parkin's ability to efficiently clear damaged mitochondria: protective effects of rapamycin

Almas Siddiqui,Ingrid Hanson,Julie K Andersen

doi:10.3109/10715762.2012.662277

Almas Siddiqui, Ingrid Hanson + Show 1 more

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https://doi.org/10.3109/10715762.2012.662277

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Abstract

Increased oxidative stress in the Parkinsonian substantia nigra is believed to contribute to neurodegeneration, in part due to regionally elevated levels of the enzyme monoamine oxidase B (MAO-B). Increased oxidative stress has also been reported to be associated with the inhibition of E3 ligase activity of the Parkinson's disease-related protein parkin. In an inducible MAO-B cell model, losses in parkin E3 ligase activity were found to occur in conjunction with reduced mitochondrial turnover and decreased mitochondrial function, although this did not inhibit parkin's ability to translocation to damaged mitochondria. The mTOR inhibitor rapamycin was found to restore both mitophagy and mitochondrial function in these cells. These data suggest that MAO-B induction can interfere with mitochondrial quality control via losses in parkin activity that in turn impact on mitochondrial turnover. Rapamycin may be an effective means of counteracting the effects of lost parkin function by independently enhancing autophagic removal of damaged mitochondria.

Highlights

Studies in both post-mortem patient tissues and Parkinsonian animal models have provided strong evidence supporting the involvement of oxidative stress in the progression of Parkinson’s disease (PD)
We first assessed whether monoamine oxidase B (MAO-B) elevation had effects on parkin E3 ligase function that could prevent the enzyme from ubiquitin-tagging dysfunctional mitochondria for lysosomal degradation
Rapamycin treatment in the context of either MAO-B induction or depolarization appeared to result in increased mitochondrial parkin levels, which were additive in combination

Summary

Introduction

Studies in both post-mortem patient tissues and Parkinsonian animal models have provided strong evidence supporting the involvement of oxidative stress in the progression of Parkinson’s disease (PD). One possible source of increased oxidative stress are elevations in brain monoamine oxidase B (MAO-B) levels, which have been demonstrated to increase with age and in association with neurodegenerative disease both in humans and in mice [12,13]. It has been postulated that age-related increases in MAO-B activity may contribute to cellular neurodegeneration in the brain due to corresponding increases in H2O2 production [10]. MAO-B catalysed ROS production has been suggested to contribute to age-related increases in mitochondrial damage, in the substantia nigra (SN), a brain region, which displays preferential neurodegeneration in PD [19]. Mitochondrial dysfunction has long been implicated in the pathogenesis of idiopathic PD [8]

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