Biomolecular Modifications Linked to Oxidative Stress in Amyotrophic Lateral Sclerosis: Determining Promising Biomarkers Related to Oxidative Stress

Round 1

Reviewer 1 Report

Hosaka and coauthors provide an extensive analysis of possible of new possible biomarkers for ALS considering both RNA, and proteins. While the effects of oxidative stress in ALS have been described before, the attempt of identify new biomarkers in this contest is innovative. 

Considering the lack of an effective cure for ALS and reliable biomarkers, except genetic tests for familial ALS, which account for only 10%, this review could be really useful for future studies summarizing the literature on Oxidative stress damages in ALS patients.  

The paper is well written and the way the review is organized makes it easy to follow, and the table helps in the visualization of the identified biomarkers.

Author Response

We thank the reviewer for valuable comment.

Author Response File: Author Response.doc

Reviewer 2 Report

The paper authored by Hosaka, et al. reviews the biomolecular modifications caused by oxidative stress and their indication for therapeutic therapy and diagnosis in the context of amyotrophic lateral sclerosis. The paper is well organized and written, as well as providing readers good information regarding this topic. I recommend acceptation of the paper with minor revisions.

1. The first paragraph of section 2 mentions the relationship between oxidative stress and neurodegenerative disease, and its indications for therapy and biomarker. The content is repetitive with some in the "Introduction". Please re-organize the content to avoid repetition.
2. line 75-78, the sentence is hard to understand. It is not clear by the sentence why oxidative stress was considered for ALS because of the SOD-1.
3. line 174, please explain the function of "p53 activity".
4. line 225-226, "increase the expression of markers of ROS damage and nucleic acid damage". It would be helpful to explicitly list a few examples of the markers. 

Author Response

1. The first paragraph of section 2 mentions the relationship between oxidative stress and neurodegenerative disease, and its indications for therapy and biomarker. The content is repetitive with some in the "Introduction". Please re-organize the content to avoid repetition.

We thank the reviewer for valuable comment. As some contents are repetitive in the introduction section, we modified the first sentences in the first paragraph of section 2 (Page 3, line110-112 in the revised manuscript) as follows.

Page 3, line110-112 in the revised manuscript

“As described in the introduction section, aging leads to increased oxidative stress and the brain is highly susceptible to ROS damage, whereas the function of antioxidant systems declines with age”

1. line 75-78, the sentence is hard to understand. It is not clear by the sentence why oxidative stress was considered for ALS because of the SOD-1.

We thank the reviewer for valuable comment. To avoid reader’s misunderstanding, we modified the sentences (Page 2, line 74-78 in the revised manuscript) as follow.

Page 2, line 74-78 in the revised manuscript

“The ALS-associated gene, superoxide dismutase 1 (SOD-1), an enzyme that converts superoxide radicals into hydrogen peroxide, was identified in 1993 [14]. Then, although a large number of pathogenic hypotheses have been proposed, oxidative stress has been considered one of the pathogenic hypotheses in ALS [15].”

1. line 174, please explain the function of "p53 activity".

We thank the reviewer for valuable comment. The increased p53 activity results in apoptosis, therefore, we modified the sentences (Page 4, line 169-171 in the revised manuscript) as follow to avoid reader’s misunderstanding.

Page 4, line 169-171 in the revised manuscript

“Moreover, higher levels of oxidative DNA damage and impairment of DNA repair pathways have been shown to lead to increased p53 activity, ultimately resulting in apoptosis.”

1. line 225-226, "increase the expression of markers of ROS damage and nucleic acid damage". It would be helpful to explicitly list a few examples of the markers. 

We thank the reviewer for valuable comment. To deepen reader’s understanding, we added a few examples of the markers in the sentences (Page 5, line 220-223 in the revised manuscript) as follow.

Page 5, line 220-223 in the revised manuscript

“Moreover, postmortem brain tissues from patients with neurodegenerative diseases have been reported to increase the expression of markers of ROS damage and nucleic acid damage, including glutathione (GSH) and 8-hydroxy-2’-deoxyguanosine (8-OHdG)”

Author Response File: Author Response.docx