Abstract
Amyotrophic lateral sclerosis (ALS) caused by mutation of superoxide dismutase 1 (SOD1), affects various cellular processes and results in the death of motor neurons with fatal defects. Currently, several neurological disorders associated with DNA damage are known to directly induce neurodegenerative diseases. In this research, we found that cytoplasmic restriction of SOD1G93A, which inhibited the nucleic translocation of SOD1WT, was directly related to increasing DNA damage in SOD1- mutated ALS disease. Our study showed that nucleic transport of DNA repair- processing proteins, such as p53, APEX1, HDAC1, and ALS- linked FUS were interfered with under increased endoplasmic reticulum (ER) stress in the presence of SOD1G93A. During aging, the unsuccessful recognition and repair process of damaged DNA, due to the mislocalized DNA repair proteins might be closely associated with the enhanced susceptibility of DNA damage in SOD1- mutated neurons. In addition, the co-expression of protein disulphide isomerase (PDI) directly interacting with SOD1 protein in neurons enhances the nucleic transport of cytoplasmic- restricted SOD1G93A. Therefore, our results showed that enhanced DNA damage by SOD1 mutation-induced ALS disease and further suggested that PDI could be a strong candidate molecule to protect neuronal apoptosis by reducing DNA damage in ALS disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is a well-known motor neurone disease, resulting in a decrease in the number of upper and lower motor neurons
As previously reported in the cell culture and animal model, mutated superoxide dismutase 1 (SOD1) is mainly located in the cytoplasm, whereas, SOD1WT is present in the whole cellular area [9]
Our study showed that cytoplasmic segregation of histone deacetylase 1 (HDAC1) and APEX1 interfered the localization of XRCC1, OGG1, and PARP1 in SOD1G93A genotype neurons was similar to that in WT
Summary
Amyotrophic lateral sclerosis (ALS) is a well-known motor neurone disease, resulting in a decrease in the number of upper and lower motor neurons. Unlike other neuronal diseases, such as Parkinson’s, Alzheimer’s and Huntington disease, ALS is a relatively rare neurological disease, but it results in the serious loss of vital within five years [1,2]. Alongside the common symptoms of the disease, such as rapid loss of muscle power, atrophy and paralysis, respiratory failure, due to dysfunctional respiratory muscles eventually results in the death of the patient. ALS (fALS), is due to genetic disorders, such as gene mutations [4,5]. Several mutations in various genes, including superoxide dismutase 1 (SOD1), fused in sarcoma (FUS) TAR DNA-binding protein
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