Emerging Evidence of Golgi Stress Signaling for Neuropathies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Emerging Evidence of Golgi Stress Signaling for Neuropathies

 

The topic of the paper as a cellular and molecular neuroscientist was really interesting for me to read. However, the authors, have not done justice to presentation of different findings in this field which looks to be lot. The manuscript suffers from poor writing w.r.t connecting sentences, presenting different findings, and making a story on the topic. Also, authors have no views of their own w.r.t their own questions, suggestions etc. on this topic they are just writing the findings in this field without highlighting the importance of these findings in neurodegeneration.in this current form, I am not able to accept the manuscript as the whole manuscript needs to re-written to address the above points.

 

 

 

Comments:

 

1.     In line no. 12, sentence “Golgi stress signaling is….” Not connected with previous sentence.

2.     Line no. 15-17: Sentence should be written in a matter where it should the role of golgi stress signaling in the different pathologies mentioned from 15-17.

3.      Line 67 and 66 are not connected, either rewrite the line no. 67 or connect lines 67 and 66

4.     Lin no 90-113 explains about the stress mechanisms in the Golgi complex. The whole paragraph is written in a very complex manner and is hard to understand. Please rewrite this whole paragraph, give paragraph break in this pargraph and write about golgi stress and its role in causing induction of that particular signaling in the golgi stress pathway.

5.     Line no.122-125; Why the authors have written about APP and Beta-site AP when they have dedicated a separate heading for AD and PD?

6.     Line no.162-165: why the authors have written about PD alongwith AD when there is just one paper  where they have cited about PD and that also they have not explained?. What does the audience for PD will gain here?. Please remove PD based sentence here from line no:162-165?

7.     Line no.166:Needs a parabreak.

8.     Line no.170-Line:200: Is like reading different papers findings in one line; with authors not able to give any connections in between these sentences.I suggest authors to read good review papers to understand review paper using different paper findings. Please re-write this whole paragraph.

9.     Line no. 214-241: Again the same mistake as done in point 8. No connection between sentences, its like reading different paper one line findings. Poorly written, needs to rewritten.

10.  Lin 264-Line 301 is same as points 8 and 9:non-comprehendeble wr.t. the presentation of different findings like how they are linked with each other, connecting the sentences with each other and to the golgi stress.

Comments on the Quality of English Language

English is understandable at many places, but at few places is very complex which I have mentioned in my report and hence needs to be changed.

Author Response

Responses to Reviewer #1’s comments

We would like to thank the reviewer for their very valuable comments.

 

The topic of the paper as a cellular and molecular neuroscientist was really interesting for me to read. However, the authors, have not done justice to presentation of different findings in this field which looks to be lot. The manuscript suffers from poor writing w.r.t connecting sentences, presenting different findings, and making a story on the topic. Also, authors have no views of their own w.r.t their own questions, suggestions etc. on this topic they are just writing the findings in this field without highlighting the importance of these findings in neurodegeneration.in this current form, I am not able to accept the manuscript as the whole manuscript needs to re-written to address the above points.

 

We thank the reviewer for pointing out that we do justice to this field—we agree with these comments. We focused on connecting sentences, presenting different findings, and creating a story so that the manuscript could be improved.

We have responded to each comment below.

1. In line no. 12, sentence “Golgi stress signaling is....” Not connected with previous sentence.

Thank you for your valuable comments. We have rewritten the abstract section so that there is a connection between the sentences before and after.

 

2. Line no. 15-17: Sentence should be written in a matter where it should the role of golgi stress signaling in the different pathologies mentioned from 15-17.

Thank you for your valuable comments. We have added to the abstract section the role of Golgi stress signaling.

 

3. Line 67 and 66 are not connected, either rewrite the line no. 67 or connect lines 67 and 66

Thank you for your valuable comments. We have added to the line no. 66 and 67.

 

4. Lin no 90-113 explains about the stress mechanisms in the Golgi complex. The whole paragraph is written in a very complex manner and is hard to understand. Please rewrite this whole paragraph, give paragraph break in this pargraph and write about golgi stress and its role in causing induction of that particular signaling in the golgi stress pathway.

Thank you for your valuable comments. We have rewritten “the Golgi Stress Response” section.

 

5. Line no.122-125; Why the authors have written about APP and Beta-site AP when they have dedicated a separate heading for AD and PD?

Thank you for your valuable comments. We have added to and revised the AD and PD sections on APP and β-site AP.

 

6. Line no.162-165: why the authors have written about PD alongwith AD when there is just one paper where they have cited about PD and that also they have not explained?. What does the audience for PD will gain here?. Please remove PD based sentence here from line no:162-165?

Thank you for your valuable comments. We have removed the sentence about PD from line no.162-165.

 

7. Line no.166:Needs a parabreak.

Thank you for your valuable comments. We have included a para before line no.166.

 

8. Line no.170-Line:200: Is like reading different papers findings in one line; with authors not able to give any connections in between these sentences.I suggest authors to read good review papers to understand review paper using different paper findings. Please re-write this whole paragraph.

Thank you for your valuable comments. We have rewritten line no.170-200.

 

9. Line no. 214-241: Again the same mistake as done in point 8. No connection between sentences, its like reading different paper one line findings. Poorly written, needs to rewritten.

Thank you for your valuable comments. We have rewritten line no.214-241.

 

10. Lin 264-Line 301 is same as points 8 and 9:non- comprehendeble wr.t. the presentation of different findings like how they are linked with each other, connecting the sentences with each other and to the golgi stress.

Thank you for your valuable comments. We have rewritten line no.264-301.

 

Other modifications and a summary of modified figures:

1. All of the modified sentences in the present manuscript are indicated by red font.
2. We have also carefully corrected the typing and grammatical mistakes throughout the manuscript with the help of a native English–speaking professional scientific editor (Chris Rowthorn Company, Limited).

 

We are very grateful for this reviewer’s input, which has enabled us to strengthen our arguments regarding Golgi stress and neurodegenerative diseases.

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to Authors

 

This work points out exhaustively how the Golgi apparatus stress is correlated in major neurological disorders. First of all, authors describe accurately the central role of this apparatus in physiological cellular process. After, a numerous pathogenetic roles of the apparatus in various neurological disorders have taken into account.

However, in this study some revision is needed:

 

1.     Introduction

Line 29 to 31: The whole sentence, even if a citation is present, should be better clarified.

 

Line 41 to 44: Authors should better explain the correlation between ER and Golgi stress.

2.     The Role of the Golgi Apparatus

Line 77 to 31. The role of cytoplasmic dynein in Golgi positioning and function should be better explained.

 

     4. Effect of Golgi Stress on Neuropathies

Line 139 to 142: This sentence should be better explained.

 

Line 157 to 159: The connection between Golgi fragmentation and Caspase-3 activation need to be elucidated.

 

Line 172: The sentence describing the use of neuroblastoma cell line can be ameliorated by adding other in vitro experimental models.

 

Line 243: The Golgi stress signaling is implicated in the pathogenic mechanism of ALS.  Are there other mechanisms? If so, author should describe them.

 

 Line 247: Dot after “membrane”.  

Author Response

Responses to Reviewer #2’s comments

We would like to thank the reviewer for the very valuable comments.

 

This work points out exhaustively how the Golgi apparatus stress is correlated in major neurological disorders. First of all, authors describe accurately the central role of this apparatus in physiological cellular process. After, a numerous pathogenetic roles of the apparatus in various neurological disorders have taken into account.

However, in this study some revision is needed:

 

We thank the reviewer for pointing out that we do justice to this field—we agree with these comments. We focused on connecting sentences, presenting different findings, and creating a story so that the manuscript could be improved.

We have responded to each comment below.

1. Introduction

Line 29 to 31: The whole sentence, even if a citation is present, should be better clarified.

Line 41 to 44: Authors should better explain the correlation between ER and Golgi stress.

Thank you for your valuable comments. We have rewritten line no.29-31 and 41-44.

 

2. The Role of the Golgi Apparatus

Line 77 to 31. The role of cytoplasmic dynein in Golgi positioning and function should be better explained.

Thank you for your valuable comments. We have rewritten line no.77-78.

 

4. Effect of Golgi Stress on Neuropathies

Line 139 to 142: This sentence should be better explained.

Line 157 to 159: The connection between Golgi fragmentation and Caspase-3 activation need to be elucidated.

Line 172: The sentence describing the use of neuroblastoma cell line can be ameliorated by adding other in vitro experimental models.

Line 243: The Golgi stress signaling is implicated in the pathogenic mechanism of ALS. Are there other mechanisms? If so, author should describe them.

Line 247: Dot after “membrane”.

 

Thank you for your valuable comments. We have rewritten all of the sentences in the sections noted.

 

Other modifications and a summary of modified figures:

1. All of the modified sentences in the present manuscript are indicated by red font.
2. We have also carefully corrected the typing and grammatical mistakes throughout the manuscript with the help of a native English–speaking professional scientific editor (Chris Rowthorn Company, Limited).

 

We are very grateful for this reviewer’s input, which has enabled us to strengthen our arguments regarding Golgi stress and neurodegenerative diseases.

Reviewer 3 Report

Comments and Suggestions for Authors

The Golgi apparatus, a crucial intracellular organelle, plays a pivotal role in modifying cellular cargo during its journey from the nucleus through the endoplasmic reticulum to the plasma membrane and extracellular space. This review gives an overview of the general functions of the Golgi and delves into Golgi stress signaling, before exploring the involvement of Golgi stress in disease. The review extends its scope from major conditions like Alzheimer's disease, Parkinson's disease, and Huntington's disease to various diseases such as hypomyelinating leukodystrophy, frontotemporal spectrum disorder/amyotrophic lateral sclerosis, microcephaly, Wilson's disease, and prion disease. While detailing Golgi stress signaling pathways, the review highlights the unclear transmission from the Golgi to the nucleus, contrasting it with the well-understood PERK and MAPK pathways involved in cellular maintenance and Golgi stress. Notably, distinct Golgi stress pathways are identified in Huntington's disease compared to Alzheimer's and Parkinson's diseases. The review concludes by emphasizing the potential major Golgi stress-inducing factors shared among diseases with similar pathologies.

The review is well written, informative and clearly structured. The figures provide a helpful addition to the written text. The topic of the review is timely, with 25% of the citations referring to papers published within the last 3 years. The references are appropriate for the topic. The authors provide a comprehensive overview over the different pathways involved in Golgi stress, link Golgi stress pathways to neurodegenerative disease and compare Golgi stress between a broad range of different neuropathies. In summary, the review will provide the readership of Neurology International with comprehensive up-to-date information on Golgi stress in neuropathological disease.

I recommend for publication pending minor modifications:

1)    At the top of figure 1 the word Ca2+ overlaps with the downward error. Could authors please correct that.

2)    Sulfate is abbreviated SO4, which is an unfortunate choice. Could authors please either use the expression “sulfate” or use the appropriate chemical version of the ion, which is SO₄^2-.

3)    In figures 4 and 5, the writing placed on top of the drawing is sometimes framed (boxed), sometimes not. Maybe authors could frame all writing to achieve a more uniform look to their figures.

Author Response

Responses to Reviewer #3’s comments

We would like to thank the reviewer for the very valuable comments.

 

The Golgi apparatus, a crucial intracellular organelle, plays a pivotal role in modifying cellular cargo during its journey from the nucleus through the endoplasmic reticulum to the plasma membrane and extracellular space. This review gives an overview of the general functions of the Golgi and delves into Golgi stress signaling, before exploring the involvement of Golgi stress in disease. The review extends its scope from major conditions like Alzheimer's disease, Parkinson's disease, and Huntington's disease to various diseases such as hypomyelinating leukodystrophy, frontotemporal spectrum disorder/amyotrophic lateral sclerosis, microcephaly, Wilson's disease, and prion disease. While detailing Golgi stress signaling pathways, the review highlights the unclear transmission from the Golgi to the nucleus, contrasting it with the well-understood PERK and MAPK pathways involved in cellular maintenance and Golgi stress. Notably, distinct Golgi stress pathways are identified in Huntington's disease compared to Alzheimer's and Parkinson's diseases. The review concludes by emphasizing the potential major Golgi stress- inducing factors shared among diseases with similar pathologies.

The review is well written, informative and clearly structured. The figures provide a helpful addition to the written text. The topic of the review is timely, with 25% of the citations referring to papers published within the last 3 years. The references are appropriate for the topic. The authors provide a comprehensive overview over the different pathways involved in Golgi stress, link Golgi stress pathways to neurodegenerative disease and compare Golgi stress between a broad range of different neuropathies. In summary, the review will provide the readership of Neurology International with comprehensive up-to-date information on Golgi stress in neuropathological disease.

 

We thank the reviewer for pointing out that we do justice to this field—we agree with these comments. We focused on connecting sentences, presenting different findings, and creating a story so that the manuscript could be improved.

We have responded to each comment below.

I recommend for publication pending minor modifications:

1) At the top of figure 1 the word Ca2+ overlaps with the downward error. Could authors please correct that.

Thank you for your valuable comments. We have corrected the figure 1 where noted.

 

2) Sulfate is abbreviated SO4, which is an unfortunate choice. Could authors please either use the expression “sulfate” or use the appropriate chemical version of the ion, which is SO42-.

Thank you for your valuable comments. We have rewritten all the parts we listed as SO₄ to the ionic version, which is SO₄^2-.

 

3) In figures 4 and 5, the writing placed on top of the drawing is sometimes framed (boxed), sometimes not. Maybe authors could frame all writing to achieve a more uniform look to their figures.

Thank you for your valuable comments. We have added frames to all figures.

 

Other modifications and a summary of modified figures:

1. All of the modified sentences in the present manuscript are indicated by red font.
2. We have also carefully corrected the typing and grammatical mistakes throughout the manuscript with the help of a native English–speaking professional scientific editor (Chris Rowthorn Company, Limited).

 

We are very grateful for this reviewer’s input, which has enabled us to strengthen our arguments regarding Golgi stress and neurodegenerative diseases.

Reviewer 4 Report

Comments and Suggestions for Authors

To enhance the manuscript's impact, I suggest a more detailed delineation of molecular mechanisms underlying Golgi stress and their disease-specific consequences. Clarifying causality versus correlation with disease states would also be beneficial. Expanding on therapeutic insights with current research and clinical trials could provide a meaningful translational dimension. Please ensure clarity in terminology for a multidisciplinary audience and update your references to reflect the latest findings. I believe these revisions will significantly bolster the manuscript's contribution to the field.

Comments:

Specificity in the Mechanisms of Golgi Stress:

• The manuscript would benefit from a more detailed explanation of the molecular pathways leading to Golgi stress in the context of each neurodegenerative disease. While the general pathways are mentioned, the exact triggers and consequences of Golgi stress within neuronal cells need further elaboration.
• For instance, the manuscript discusses Golgi fragmentation in Alzheimer's and Parkinson’s diseases but does not thoroughly explore the cellular consequences of this fragmentation. Does Golgi fragmentation disrupt all trafficking pathways, or are specific cargo proteins more affected?

Data Correlation and Causality:

• The manuscript often mentions correlations between Golgi stress markers and disease states. However, it lacks a critical discussion on whether Golgi stress is a direct cause, a contributing factor, or a symptom of these diseases. Providing a more nuanced discussion on this topic would enhance the manuscript's depth.
• There is a need for a clearer distinction between in vitro and in vivo findings and how these different experimental setups might influence the interpretation of results related to Golgi function in disease.

Inclusion of Quantitative Data and Meta-Analyses:

• Where available, the inclusion of quantitative data or meta-analyses that support the role of Golgi stress in neurodegenerative diseases could strengthen the arguments presented.
• The manuscript would benefit from a table summarizing key studies that quantitatively link Golgi stress markers to disease progression or severity in clinical settings.

Therapeutic Implications:

• While the manuscript touches on potential therapeutic interventions, these sections are somewhat speculative. A more rigorous analysis of current therapeutic strategies targeting the Golgi apparatus, including any clinical trials, would be valuable.
• The manuscript should address the translational gap between understanding Golgi stress and developing therapeutics. What are the challenges, and how might recent discoveries help overcome them?

Figure and Diagram Clarifications:

• Figures illustrating Golgi stress pathways should include a clearer indication of where specific proteins and pathways fit into the broader cellular context.
• Diagrams depicting the Golgi apparatus in a diseased state should be directly contrasted with those in a healthy state for clearer visualization of the changes occurring.

Technical Details and Clarifications:

• The manuscript occasionally uses technical terms and abbreviations without proper introduction or explanation. Each term should be clearly defined upon first use to ensure readability across disciplines.
• In discussing Golgi-related proteins, such as GRASP55 and its role in Huntington's disease, the manuscript should clarify how the protein's normal function is altered and the implications for Golgi morphology and function.

Review and Conclusion Balance:

• The manuscript's conclusion should synthesize the main findings into a coherent narrative that highlights the most promising areas for future research.
• A discussion on the limitations of the current understanding of Golgi stress in neurodegenerative diseases would be helpful. How might future research address these gaps?

References and Citations:

• Some sections appear to draw heavily on a subset of the literature. The manuscript should ensure that it encompasses a wide range of studies, avoiding over-reliance on specific research groups or viewpoints.
• References should be up-to-date, and any seminal work that established the field’s foundational knowledge must be appropriately acknowledged.

 

 

Author Response

Responses to Reviewer #4’s comments

We would like to thank the reviewer for the very valuable comments.

 

To enhance the manuscript's impact, I suggest a more detailed delineation of molecular mechanisms underlying Golgi stress and their disease-specific consequences. Clarifying causality versus correlation with disease states would also be beneficial. Expanding on therapeutic insights with current research and clinical trials could provide a meaningful translational dimension. Please ensure clarity in terminology for a multidisciplinary audience and update your references to reflect the latest findings. I believe these revisions will significantly bolster the manuscript's contribution to the field.

 

We thank the reviewer for pointing out that we do justice to this field—we agree with these comments. We focused on connecting sentences, presenting different findings, and creating a story so that the manuscript could be improved.

We have responded to each comment below.

Comments:

Specificity in the Mechanisms of Golgi Stress:

The manuscript would benefit from a more detailed explanation of the molecular pathways leading to Golgi stress in the context of each neurodegenerative disease. While the general pathways are mentioned, the exact triggers and consequences of Golgi stress within neuronal cells need further elaboration.

For instance, the manuscript discusses Golgi fragmentation in Alzheimer's and Parkinson’s diseases but does not thoroughly explore the cellular consequences of this fragmentation. Does Golgi fragmentation disrupt all trafficking pathways, or are specific cargo proteins more affected?

Thank you for your valuable comments. We have added a note on the triggers and consequences of Golgi stress.

 

Data Correlation and Causality:

The manuscript often mentions correlations between Golgi stress markers and disease states. However, it lacks a critical discussion on whether Golgi stress is a direct cause, a contributing factor, or a symptom of these diseases. Providing a more nuanced discussion on this topic would enhance the manuscript's depth.

There is a need for a clearer distinction between in vitro and in vivo findings and how these different experimental setups might influence the interpretation of results related to Golgi function in disease.

Thank you for your valuable comments. We noted whether Golgi stress markers are a cause or a contributor to the disease.

 

Inclusion of Quantitative Data and Meta-Analyses:

Where available, the inclusion of quantitative data or meta- analyses that support the role of Golgi stress in neurodegenerative diseases could strengthen the arguments presented.

The manuscript would benefit from a table summarizing key studies that quantitatively link Golgi stress markers to disease progression or severity in clinical settings.

Thank you for your valuable comments. We carefully searched but found no available metadata.

 

Therapeutic Implications:

While the manuscript touches on potential therapeutic interventions, these sections are somewhat speculative. A more rigorous analysis of current therapeutic strategies targeting the Golgi apparatus, including any clinical trials, would be valuable.

The manuscript should address the translational gap between understanding Golgi stress and developing therapeutics. What are the challenges, and how might recent discoveries help overcome them?

Thank you for your valuable comments. We have added to this manuscript on therapeutic strategies targeting the Golgi.

 

Figure and Diagram Clarifications:

Figures illustrating Golgi stress pathways should include a clearer indication of where specific proteins and pathways fit into the broader cellular context.

Diagrams depicting the Golgi apparatus in a diseased state should be directly contrasted with those in a healthy state for clearer visualization of the changes occurring.

Thank you for your valuable comments. We added Golgi stress of health status to figure 4.

 

Technical Details and Clarifications:

The manuscript occasionally uses technical terms and abbreviations without proper introduction or explanation. Each term should be clearly defined upon first use to ensure readability across disciplines.

In discussing Golgi-related proteins, such as GRASP55 and its role in Huntington's disease, the manuscript should clarify how the protein's normal function is altered and the implications for Golgi morphology and function.

Thank you for your valuable comments. We have added a note on the association between GRASP55 and Huntington's disease and the altered function of GRASP55.

 

Review and Conclusion Balance:

The manuscript's conclusion should synthesize the main findings into a coherent narrative that highlights the most promising areas for future research.

A discussion on the limitations of the current understanding of Golgi stress in neurodegenerative diseases would be helpful. How might future research address these gaps?

Thank you for your valuable comments. We have added a discussion of the limitations of our current understanding of Golgi stress in neurodegenerative diseases in the Conclusions section.

 

References and Citations:

Some sections appear to draw heavily on a subset of the literature. The manuscript should ensure that it encompasses a wide range of studies, avoiding over- reliance on specific research groups or viewpoints.

References should be up-to-date, and any seminal work that established the field’s foundational knowledge must be appropriately acknowledged.

Thank you for your valuable comments. We have carefully scrutinized our references and have clearly cited representative studies.

 

Other modifications and a summary of modified figures:

1. All of the modified sentences in the present manuscript are indicated by red font.
2. We have also carefully corrected the typing and grammatical mistakes throughout the manuscript with the help of a native English–speaking professional scientific editor (Chris Rowthorn Company, Limited).

 

We are very grateful for this reviewer’s input, which has enabled us to strengthen our arguments regarding Golgi stress and neurodegenerative diseases.

Round 2

Reviewer 4 Report

Comments and Suggestions for Authors

The authors have satisfactorily answered my queries.