Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models

Abstract

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.

Increase in Expression Levels and Resistance to Sulfhydryl Oxidation of Peroxiredoxin Isoforms in Amyloid β-Resistant Nerve Cells

“…Several studies have shown that Prx expression is elevated in neurodegenerative diseases such as AD, Parkinson disease, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis (17)(18)(19)(20). However, it is not known if increased Prx expression in these diseases occurs as a general response to nerve cell death or is a protective mechanism elicited by disease-specific stimuli.…”

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

“…The first symptom of the hSOD1 mice is a fine "jittering/tremor" in one or more of the limbs, which appears at ϳ90 to 100 days of age (21,22). At later stages, the cytopathological features of the hSOD1 transgenic mice include motor neuron loss with astrocytosis, the presence of SOD1-positive inclusions including Lewy body-like hyaline inclusions/astrocyte hyline inclusions, and vacuole formation (23).…”

Oxidative Modification to Cysteine Sulfonic Acid of Cys111 in Human Copper-Zinc Superoxide Dismutase

“…Finally, an immunohistochemical study of paraffin-embedded spinal cord sections of G1H-G93A mice was performed. The G1H-G93A mice examined at 110 days of age revealed severe loss of anterior horn cells with gliosis and both Lewy body-like hyaline inclusions (LBHIs) and vacuolation pathologies (32). The anti-C111ox-SOD1 selectively labeled the LBHIs in the neuropil and in the cytoplasm of the neurons (Fig.…”

“…8, B and C). Because the most characteristic neuropathological findings in ALS model mice are LBHIs and vacuoles (32,33), the peroxidation of Cys 111 may contribute to the pathology of the degeneration/ death of FALS motor neurons. However, the amount of the Cys 111 -peroxidized SOD1 appears to be quite limited (Fig.…”