Redox regulation of autophagy in healthy brain and neurodegeneration

Abstract

Autophagy and redox biochemistry are two major sub disciplines of cell biology which are both coming to be appreciated for their paramount importance in the etiology of neurodegenerative diseases including Alzheimer’s disease (AD). Thus far, however, there has been relatively little exploration of the interface between autophagy and redox biology. Autophagy normally recycles macro-molecular aggregates produced through oxidative-stress mediated pathways, and also may reduce the mitochondrial production of reactive oxygen species through recycling of old and damaged mitochondria. Conversely, dysfunction in autophagy initiation, progression or clearance is evidenced to increase aggregation-prone proteins in neural and extraneural tissues. Redox mechanisms of autophagy regulation have been documented at the level of cross-talk between the Nrf2/Keap1 oxidant and electrophilic defense pathway and p62/sequestosome-1 (SQSTM1)-associated autophagy, at least in extraneural tissue; but other mechanisms of redox autophagy regulation doubtless remain to be discovered and the relevance of such processes to maintenance of neural homeostasis remain to be determined. This review summarizes current knowledge regarding the relationship of redox signaling, autophagy control, and oxidative stress as these phenomena relate to neurodegenerative disease. AD is specifically addressed as an example of the theme and as a promising indication for new therapies that act through engagement of autophagy pathways. To exemplify one such novel therapeutic entity, data is presented that the antioxidant and neurotrophic agent lanthionine ketimine-ethyl ester (LKE) affects autophagy pathway proteins including beclin-1 in the 3xTg-AD model of Alzheimer’s disease where the compound has been shown to reduce pathological features and cognitive dysfunction.

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

“…While their role in CRMP2 phosphorylation remains unknown, LKE administration reduces CRMP2-tubulin affinity while enhancing CRMP2-neurofilament binding. LKE treatment has been shown to delay progressive neurodegeneration in AD and ALS model mice [128,129]. From our observations, LKE has been confirmed to have a therapeutic effect in SCI and PD mouse models (unpublished observation).…”

“…WO 2014139539 A1). Interestingly, BMP signaling downstream to the transcription factor Smad1 has been shown to suppress the Decreased excitatory synaptic connectivity in posttraumatic epileptogenesis [125] and reduction in pain behavior in vivo [100] LKE CRMP2 Alters binding affinity of CRMP2 and its partners Suppressed inflammation in the AD model [127] Neuroprotection in the multiple sclerosis [128] and cerebral ischemia [129] C4RIP RhoA-CRMP4 binding Antagonizes the binding of RhoA and the N-terminus of CRMP4b…”

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…Most neurodegenerative disorders such as AD, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Friedreich's ataxia or Hungtington disease are characterized by oxidative stress and misfolded protein aggregates, so targeting both alterations has always been considered an important therapeutic approach for these diseases (Burchell et al, 2010). The ability of the Nrf2 pathway to regulate genes associated with antioxidant defense, autophagy and proteasome activation has been attracting attention to the use of Nrf2 activators as therapeutic strategies for neurodegenerative diseases (reviewed in (Hensley and Harris-White, 2015;Johnson and Johnson, 2015).…”

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway

“…Autophagy normally recycles macromolecular aggregates produced through oxidative stress-mediated pathways and may also reduce mitochondrial production of ROS through recycling of old and damaged mitochondria (Hensley and Harris-White, 2015). Thus, autophagy is thought to be an essential cellular antioxidant pathway (Giordano et al, 2014).…”