Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity

Abstract

Free radical-mediated oxidative stress, neuroinflammation, and excitotoxicity have long been considered insults relevant to the progression of Alzheimer’s disease and other aging-related neurodegenerative disorders (NDD). Among these phenomena, the significance of oxidative stress and, more generally, redox perturbations, for NDD remain ill-defined and unsubstantiated. Here, I argue that (i) free radical-mediated oxidations of biomolecules can be dissociated from the progression of NDD, (ii) oxidative stress fails as a descriptor of cellular redox states under conditions relevant to disease, and (iii) aberrant upregulation of compensatory reducing activities in neural cells, resulting in reductive shifts in thiol-based redox potentials, may be an overlooked and paradoxical contributor to disease progression. In particular, I summarize evidence which supports the view that reductive shifts in the extracellular space can occur in response to oxidant and inflammatory signals and that these have the potential to reduce putative regulatory disulfide bonds in exofacial domains of the N-methyl-d-aspartate receptor, leading potentially to aberrant increases in neuronal excitability and, if sustained, excitotoxicity. The novel reductive reprogramming hypothesis of neurodegeneration presented here provides an alternative view of redox perturbations in NDD and links these to both neuroinflammation and excitotoxicity.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

BACE1:

β-Secretase 1

DTT:

Dithiothreitol

Grx:

Glutaredoxin

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

IL-β:

Interleukin 1-β

LPS:

Lipopolysaccharide

NDD:

Neurodegenerative disease

NMDA:

N-methyl-d-aspartate

PD:

Parkinson’s disease

Prx:

Peroxiredoxin

RNOS:

Reactive nitrogen oxide species

ROS:

Reactive oxygen species

SOD-1:

Superoxide dismutase-1

TNFalpha:

Tumor necrosis factor-α

Trx:

Thioredoxin

TrxR:

Thioredoxin reductase

Txnip:

Thioredoxin-interacting protein

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Foley, T.D. Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity. Cell Mol Neurobiol 39, 577–590 (2019). https://doi.org/10.1007/s10571-019-00672-w

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Keywords

  • Excitotoxicity
  • Neurodegenerative disease
  • Neuroinflammation
  • Oxidative stress
  • Protein thiols
  • Redox signaling
  • Reductive stress