Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Neurodegenerative Disorders-An Overview

Abstract

Nitric oxide, a ubiquitous molecule found throughout the natural world, is a key molecule implicated in many central and benefic molecular pathways and has a well-established role in the function of the central nervous system, as numerous studies have previously shown. Dysregulation of its metabolism, mainly the upregulation of nitric oxide production, has been proposed as a trigger and/or aggravator for many neurological affections. Increasing evidence supports the implication of this molecule in prevalent neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. The mechanisms proposed for its neurotoxicity mainly center around the increased quantities of nitric oxide that are produced in the brain, their cause, and, most importantly, the pathological metabolic cascades created. These cascades lead to the formation of neuronal toxic substances that impair the neurons' function and structure on multiple levels. The purpose of this review is to present the main causes of increased pathological production, as well as the most important pathophysiological mechanisms triggered by nitric oxide, mechanisms that could help explain a part of the complex picture of neurodegenerative diseases and help develop targeted therapies.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; neurodegenerative disorders; nitric oxide; nitric oxide synthase; superoxide dismutase 1.

Figure 1

Degradation reaction chain of peroxynitrile (1) through the peroxynitrous acid (2) intermediate.

Figure 2

Mechanisms implicated in elevated NO generation. On the right, the excitotoxicity pathway begins from excess glutamate, which through coupling with NOS enzymes via Ca²⁺ leads to an increase in NO production. On the left, the inflammatory pathway begins with any form of acute or chronic inflammation, which through the activation of inflammatory cells, including microglia, leads to the formation of de novo iNOS. In a Ca²⁺ independent manner, iNOS increases the production of NO. Both pathways culminate in the common end result of increased RNS formation. Abbreviations: iNOS, inducible nitric oxide synthase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDAR, N-methyl-d-aspartate receptors; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; RNS, reactive nitrogen species; ↑ increase; ↓ decrease. References: [9,10,11,12,15,33,34].

Figure 3

High concentrations of NO can negatively impact cellular function either directly or through peroxynitrile. Direct actions of NO include mitochondrial inhibition through complex I inhibition and release of bonded iron from transferrin. Mitochondrial inhibition through complex I inhibition results in lowered ATP production, which increases mitochondrial permeability, leading to cytochrome c release, thus activating apoptosis. Through the release of bonded iron from transferrin, NO increases the reactivity of iron ions, and subsequently, the formation of ROS. In combination with superoxide, NO forms peroxynitrile, a toxic compound with many deleterious effects. Peroxynitrile irreversibly damages mitochondria, damages DNA and induces apoptosis, and S-Nitrosylate key cellular proteins. S-Nitrosylation of tyrosine hydroxylase leads to an increase in its function and therefore increased dopamine synthesis. As a result of increased dopamine levels, mtNOS activation will lead to the formation of extra NO, and the excess of dopamine metabolism will increase superoxide concentrations and decrease glutathione levels, leading to the formation of more peroxynitrile. S-Nitrosylation of other proteins, such as DJ-1 and PINK1, whose main roles revolve around mitochondrial integrity and cell survival, could impair these exact roles, damaging mitochondria and promoting cellular death. Another two proteins, PDI and Parkin, which are involved in protein degradation, could lose their function due to S-Nitrosylation, increasing intracellular protein accumulation, and formation of Lewy bodies. Protein aggregation inside the endoplasmic reticulum will lead to ER stress, impaired function, and release of Ca²⁺, activating nNOS, increasing NO levels. Abbreviations: ATP, adenosine triphosphate; DNA, deoxyribonucleic acid; ER, endoplasmic reticulum; mtNOS, mitochondrial nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PDI, protein disulfide isomerase; PINK1, PTEN-induced kinase 1; ROS, reactive oxygen species; ↑ increase; ↓ decrease. References: [7,9,11,13,14,15,44,67,69,70,74,75,82,83].

Figure 4

Increase in oxidative and nitrosative stress (red pathway), either through the increase formation of superoxide, decrease in ROS degradation, or increased NO concentration, represents the early stage. This increase culminates in the formation of peroxynitrile, and the S-Nitrosylation of key cellular proteins, such as PDI and TDP43, and the beginning of the prion-like stage (blue pathway). S-nitrosylated PDI and TDP43 are able to misfold wild-type SOD, causing a decrease in the ROS degradation capabilities of the neuron, further aggravating the early stage changes. Additionally, misfolded SOD and S-nitrosylated TDP43 are able to induce wild-type SOD misfolding in neighboring neurons. Finally, in the end stage (black pathway), the excessive protein accumulation, decreased DNA transcription, and direct toxicity of peroxynitrile, apoptosis occurs. Abbreviations: mSOD1, mutant copper-zinc superoxide dismutase 1; NO, nitric oxide; PDI, protein disulfide isomerase; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD1, wild-type copper-zinc superoxide dismutase 1; TDP43, TAR DNA-binding protein 43; ↑ increase; ↓ decrease. References: [15,135,137,138,140,141,143,144,145,146,147,148].