The Role of NMNAT2/SARM1 in Neuropathy Development

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript presents us with potential therapeutic targets for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a serious infliction that adds to the pre-existing distress of having to go through chemotherapy. This manuscript certainly presents a comprehensive review of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha and TIR motif-containing 1 protein (SARM1) as pivotal mediators of axonal degeneration in CIPN.

The manuscript is well-written and comprehensive, however, it is very text heavy. Incorporation of flowcharts can make it more reader-friendly. 

Lines 39-47: The authors mention three NMNAT isoenzymes. How are the functions of each isotype different from each other? is one isoenzyme more potent than others? The authors do not discuss the role of NMNAT1 and 3. Why? 

Lines 51-55: The authors mention that NMNAT2 exhibits a cancer-promoting function in certain cases. Isnt this function contradict its neuroprotective role? Please state the differences in the mechanism through which NMNAT2 promotes cancer and shows a neuroprotective role. 

Lines 158-161: The authors propose a possible way through which chemotherapy agents activate SARM1. Is there a hypothesis as to how NMNAT2 plays a role here? Or is this NMNAT2 independent? 

It would be beneficial if the authors could include a flowchart depicting the SARM1-JNKs-cJun pathway to understand the role of SARM1 in innate immunity better. 

If the authors could incorporate a table listing the various chemotherapy drugs that are known to increase SARM1 levels leading to axonal injury, their case could be strengthened significantly. 

Overall, this is a good manuscript that needs a minor revision. Although not major, I have identified a few typos and grammatical inconsistencies. I recommend a thorough proofreading and grammar check before submitting their revised manuscript. 

Author Response

Dear Editor,

We appreciate you and the reviewers for your precious time in reviewing our manuscript and providing valuable comments. It was your valuable and insightful comments that led to possible improvements in the current version. The authors have carefully considered the comments and tried our best to address every one of them. We hope the manuscript after careful revisions meet your high standards. The authors welcome further constructive comments if any. Below we provide the point-by-point responses.

Sincerely,

Dr. Olga Tarasiuk

Response to reviewer 1

Comment: Lines 39-47: The authors mention three NMNAT isoenzymes. How are the functions of each isotype different from each other? is one isoenzyme more potent than others? The authors do not discuss the role of NMNAT1 and 3. Why?

Response : We added to the review text (line 44-51) that explains the function of other NMNAT isoformes and why we concentrate our attention on NMNAT2.

Comment: Lines 51-55: The authors mention that NMNAT2 exhibits a cancer-promoting function in certain cases. Isnt this function contradict its neuroprotective role? Please state the differences in the mechanism through which NMNAT2 promotes cancer and shows a neuroprotective role.

Response : We added to the review text (line 64-78) that explains the role of NMNAT2 in cancer progression and its distinct from neuronal tissue function.

Comment: Lines 158-161: The authors propose a possible way through which chemotherapy agents activate SARM1. Is there a hypothesis as to how NMNAT2 plays a role here? Or is this NMNAT2 independent?

Response : We added to the review text (line 187-191) that explains the role of NMNAT2 in this pathway.

Comment: It would be beneficial if the authors could include a flowchart depicting the SARM1-JNKs-cJun pathway to understand the role of SARM1 in innate immunity better.

Response : We added a flowchart (Figure 3) as it has been suggested.

Comment: If the authors could incorporate a table listing the various chemotherapy drugs that are known to increase SARM1 levels leading to axonal injury, their case could be strengthened significantly.

Response : We added a table (Table 1) as it has been suggested.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript is a review article that outlines the roles of NMNAT2 and SARM1 in axonopathy, with a focus on chemotherapy-induced peripheral neuropathy. The article is well written, overall well organized, and appears to accurately represent the state of the literature. The introduction is concise and well written. Overall, the article is well done. As a minor note, many of the paragraphs contain statements such as “studies have shown…” when representing findings from a single publication. This is not a major issue, but the wording suggests to the reader that more citations would be expected than are presented. The authors may wish to re-word these statements, but they do not affect the scientific validity of the manuscript.

Author Response

Dear Editor,

We appreciate you and the reviewers for your precious time in reviewing our manuscript and providing valuable comments. It was your valuable and insightful comments that led to possible improvements in the current version. The authors have carefully considered the comments and tried our best to address every one of them. We hope the manuscript after careful revisions meet your high standards. The authors welcome further constructive comments if any. Below we provide the point-by-point responses.

Sincerely,

Dr. Olga Tarasiuk

Response to reviewer 2

Comment:  As a minor note, many of the paragraphs contain statements such as “studies have shown…” when representing findings from a single publication.

Response : Corresponding changes were made throughout the text

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors provide an updated, though somewhat descriptive, account of the roles of NMNAT2 and SARM1 in axonal degeneration in general, and then discuss implications for chemotherapy-induced neuropathies, with a side discussion of their roles in innate immunity.  The senior author, in particular, has contributed to the literature on neuropathies, but the roles of the authors in primary investigatorion on NMNAT2/SARM1 are not clear, and the manuscript occasionally seems to provide a superficial, rather than critical, evaluation of the field.  Perhaps omitting the innate immunity section, and spending more time diving into the details of crucial studies, would have strengthened this manuscript.

Comments on the Quality of English Language

As mentioned elsewhere in this review, a more critical citation of critical papers, rather than a superficial overall headline for each, would have improved the value of this manuscript.

Author Response

Dear Editor,

We appreciate you and the reviewers for your precious time in reviewing our manuscript and providing valuable comments. It was your valuable and insightful comments that led to possible improvements in the current version. The authors have carefully considered the comments and tried our best to address every one of them. We hope the manuscript after careful revisions meet your high standards. The authors welcome further constructive comments if any. Below we provide the point-by-point responses.

Sincerely,

Dr. Olga Tarasiuk

Response to reviewer 3

Comment: Perhaps omitting the innate immunity section, and spending more time diving into the details of crucial studies, would have strengthened this manuscript.

Response : As derived from literature, the role of SARM1 in the innate immune system may have a role in a complex CIPN mechanism, we believe it is important to keep the part of the review that discusses it. As suggested by the reviewer 1, we added to the text a flowchart that represents its pathway and makes this part of the text more understandable.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have considerably rewritten their manuscript.  They have chosen not to follow a substantial suggestion by reviewer 3, and therefore the manuscript is still less than optimally focused, thus somewhat diminishing this reviewer's enthusiasm.  Nevertheless, a useful review of an important topic.