The interplay between redox signalling and proteostasis in neurodegeneration: In vivo effects of a mitochondria-targeted antioxidant in Huntington's disease mice

Brígida R Pinho,Ana I Duarte,Paula M Canas,Paula I Moreira,Michael P Murphy,Jorge M.A Oliveira

doi:10.1016/j.freeradbiomed.2019.11.021

Abstract

Abnormal protein homeostasis (proteostasis), dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders, such as Huntington's (HD), Alzheimer's and Parkinson's diseases. It remains incompletely understood, however, how changes in redox signalling affect proteostasis mechanisms, including protein degradation pathways and unfolded protein responses (UPR). Here we address this open question by investigating the interplay between redox signalling and proteostasis in a mouse model of HD, and by examining the in vivo effects of the mitochondria-targeted antioxidant MitoQ. We performed behavioural tests in wild-type and R6/2 HD mice, examined markers of oxidative stress, UPR activation, and the status of key protein degradation pathways in brain and peripheral tissues. We show that R6/2 mice present widespread markers of oxidative stress, with tissue-specific changes in proteostasis that were more pronounced in the brain and muscle than in the liver. R6/2 mice presented increased levels of cytosolic and mitochondrial chaperones, particularly in muscle, indicating UPR activation. Treatment with MitoQ significantly ameliorated fine motor control of R6/2 mice, and reduced markers of oxidative damage in muscle. Additionally, MitoQ attenuated overactive autophagy induction in the R6/2 muscle, which has been associated with muscle wasting. Treatment with MitoQ did not alter autophagy markers in the brain, in agreement with its low brain bioavailability, which limits the risk of impairing neuronal protein clearance mechanisms. This study supports the hypotheses that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment in HD, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD.

Highlights

Neurodegenerative disorders often present common pathological mechanisms, including abnormal protein homeostasis, mitochondrial dysfunction, and aberrant redox signalling [1,2]
Concerning mitochondria, we focused on succinate dehydrogenase complex (SDHA), mitochondrial transcription factor A (TFAM), and Hsp60 as indicators of mitochondrial mass, biogenesis, and proteostasis, respectively [44,45,46]
Pursuing the hypothesis that the ubiquitin-proteasome system (UPS) and autophagy pathways are under redox regulation [8,50], we examined the levels of ubiquitinated proteins and autophagy markers in R6/2 and WT mice, and how these were affected by treatment with the mitochondriatargeted antioxidant MitoQ

Summary

Introduction

Neurodegenerative disorders often present common pathological mechanisms, including abnormal protein homeostasis (proteostasis), mitochondrial dysfunction, and aberrant redox signalling [1,2]. Physiological redox signalling involves the reversible oxidation of specific protein residues by reactive oxygen species (ROS), such as the H2O2 generated from superoxide produced in mitochondria and by NADPH oxidases [3,4]. The interplay between redox signalling and proteostasis is a subject under active discussion. Aberrant redox signalling may compromise the normal activity of key proteostasis effectors such as molecular chaperones [6,7] and protein degradation pathways, including the ubiquitin-proteasome. In the context of neurodegeneration, it remains incompletely understood how changes in redox signalling modulate proteostasis, cytosolic and mitochondrial unfolded protein responses (UPR), and how targeted interventions that prevent localized ROS production in mitochondria affect proteostasis. A better understanding of this interplay should contribute to develop effective treatments

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Conclusion