Abstract
Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.
Highlights
We developed an in vitro model using the mouse motor neuronal cell line NSC-34 exposed to the microenvironmental stress hydrogen peroxide (H2O2)
The present study was designed to analyze variations in gene expression that follow the exposure of NSC-34 cells, a motor neuronal cell line, to oxidative stress and to an ALSrelated superoxide dismutase 1 (SOD1) mutant
We chose to use NSC-34 cells because it is the most common cell line used in amyotrophic lateral sclerosis (ALS) research and it was described as having several morphological and physiological properties of motor neurons [31]
Summary
A common feature in both sporadic ALS and familial ALS is the presence of protein aggregates rich in ubiquitin/ubiquitin-like proteins in motor neurons. These observations support a role for the ubiquitin proteasome system and ubiquitin-like small ubiquitin-related modifier (SUMO) system in ALS physiopathology [1,2,3,4]. Accumulative oxidative damages with age induce metabolic alterations, protein aggregation, and reduced mitochondrial function [6]. Oxidative damages are a consequence of an imbalance between a production of reactive oxygen species (ROS) and the ability of motor neurons/glial cells to reduce the level of ROS. Evidence of oxidative damages in ALS includes protein, lipid, and DNA oxidation observed in spinal cord and cerebrospinal fluid from ALS patients [7,8,9,10,11]
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