Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In summary, the manuscript presents an interesting and potentially valuable approach, but it requires major revision before it can be considered for publication. The authors should focus in particular on reinforcing the experimental validation, providing a more detailed statistical analysis of the results, and streamlining the text. If these issues are addressed, the manuscript could make a meaningful contribution to the field of radiogenomics in glioblastoma.

This manuscript explores an original and under-investigated topic: the role of abnormal transcytosis mechanisms in the pathogenesis of hydrocephalus. The authors provide an extensive overview of the molecular machinery involved in vesicular transport, including SNARE proteins, NSF, alpha-SNAP, Rab proteins, and alpha-synuclein. The review also integrates insights from animal models..

The manuscript has several strengths. The topic is of interest, and the molecular focus is well-developed and comprehensive. The references appeare appropriate to the best of my knowledge, and the paper is informative for readers interested in the cellular and molecular underpinnings of hydrocephalus.

However, I believe the manuscript in its current form requires major revisions before it can be considered for publication.

Major points to address:

• The text is highly descriptive but lacks critical synthesis. The review would benefit from a more integrative approach, highlighting the overarching mechanisms or unifying hypotheses.
• The language is occasionally repetitive and would benefit from professional editing to improve clarity and readability.
• The clinical implications, though mentioned, are underdeveloped. A more detailed and structured section on translational or therapeutic perspectives would greatly enhance the manuscript.
• Along with citation 4 in the introduction, speaking about shunt diversion or ETV, I would cite this recent paper PMID: 38759789
• Given the density of molecular content, the inclusion of summary tables or diagrams to compare pathways and mechanisms would improve accessibility for the reader.

Author Response

For Review Article: Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Response to Reviewer Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

 

2. Questions for General Evaluation

General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		Many thanks
Is the work well organized and comprehensively described?		Many thanks
Is the work scientifically sound and not misleading?		Many thanks
Are there appropriate and adequate references to related and previous work?		Many thanks
Is the English used correct and readable?	The English is fine and does not require any improvement.	Many thanks

 

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1

If these issues are addressed, the manuscript could make a meaningful contribution to the field of radiogenomics in glioblastoma.

Response 1

We thank the reviewer for the comment, however, this paper is not discussing the radiogenomics of glioblastoma in any way.

 

Comment 2

The text is highly descriptive but lacks critical synthesis. The review would benefit from a more integrative approach, highlighting the overarching mechanisms or unifying hypotheses.

Response 2

In the introduction we have explained that “Our specific goal is to identify targets that modify macromolecular clearance and develop effective pharmacological interventions to relieve hydrocephalus.”

This has been re-iterated in the conclusion and we have added “particularly possible pharmacological strategies focusing on improving or promoting transcytosis mechanisms to improve the clearance of macromolecules”.

We are exploring transcytosis as a mechanism to transport macromolecules out of the ventricles and this can be used as a strategy to develop a pharmacological treatment for hydrocephalus.

 

Comment 3

The language is occasionally repetitive and would benefit from professional editing to improve clarity and readability.

Response 3

We have made several changes to the text, highlighted in yellow, hoping to improve the authenticity and clarity of the text.

 

Comment 4

The clinical implications, though mentioned, are underdeveloped. A more detailed and structured section on translational or therapeutic perspectives would greatly enhance the manuscript

Response 4

The conclusion has been amended to include further details on the possible therapeutic targets that can come out of studying the link between hydrocephalus and transcytosis: “The process of transcellular transport is complex and has many proteins and factors that regulate it. It has been shown that the pathogenesis of hydrocephalus is a result of poor macromolecular clearance out of the ventricles. This review reveals that abnormal transcytosis can result in hydrocephalus and therefore transcytosis could be one of the mechanisms that help clear these macromolecules. However, very little research has been done looking at the link between transcytosis and Hydrocephalus formation. Thus, further work in this area can help shed light on the mechanisms behind the formation of hydrocephalus and lead to a better understanding of the disease. It can also lead to better management strategies for hydrocephalus, particularly possible pharmacological strategies focusing on improving or promoting transcytosis mechanisms to improve the clearance of macromolecules.”

 

Comment 5

Along with citation 4 in the introduction, speaking about shunt diversion or ETV, I would cite this recent paper PMID: 38759789

Response 5

We have reviewed the suggested paper and found that it has to do with Normal Pressure Hydrocephalus and it has very little relevance to transcytosis mechanisms. We would have been happy to add it if it had any links to transcytosis, however, in this instance as it does not, we will not be adding this citation to the paper.

 

Comment 6

Given the density of molecular content, the inclusion of summary tables or diagrams to compare pathways and mechanisms would improve accessibility for the reader.

Response 6

Table 5 has been added to the end of the article, prior to the conclusion to act as a summary of the main contents of the body of the article.

 

4. Response to Comments on the Quality of English Language

N/A

 

5. Additional clarifications

None.

Please also see the attachement. 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The review entitled “Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review” describes the state of the art of the Hydrocephalus disease. It provides a thorough review of the mechanisms involved in transcytosis and their potential link to hydrocephalus, covering various proteins involved such as SNARE, Alpha-SNAP and NSF, Alpha-synuclein, T-SNAREs and v-SNAREs, Munc18 and Rab proteins, possible protein mutations and the pathways in which they have been described to be involved in hydrocephalus disease.

The review is well written and organized, however there are some items that should be improved before publication:

• There is not information regarding the epidemiology of the disease.
• There are numerous abbreviations that are not described in the text, beginning from the abstract. Since some abbreviations are of utmost importance in the review, they should be described the first time the appear in the abstract, in the main text and in the figures’ captions. Some of them are: SNARE, SNAP, HYH, CSPa, HSP, PCC MRI, Dgl5(-/-), L1CAM, LKB1, AMPK etc.
• There is a mistake in figures’ numbering since the first figure has been numbered as figure 2 but there is not figure 1 in the manuscript. And the same problem is shown with the tables since table 2 is missing.
• Information contained in figure 5 is not legible at all and thus the layout of all the information contained should be presented in other way to make the understanding of what is included in the figure possible. The same problem is present in figure 14.
• Figure 9 contains words that are not English.

Author Response

For Review Article: Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Response to Reviewer Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

 

2. Questions for General Evaluation

General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		Many thanks
Is the work well organized and comprehensively described?		Many thanks
Is the work scientifically sound and not misleading?		Many thanks
Are there appropriate and adequate references to related and previous work?		Many thanks
Is the English used correct and readable?	The English is fine and does not require any improvement.	Many thanks

 

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1

There is not information regarding the epidemiology of the disease

Response 1

The following has been added to the article: “Hydrocephalus displays a bimodal age distribution; being most common in infancy and amongst the elderly population [2]. The global prevalence of hydrocephalus is about 85:100,000; however in children the prevalence is 88:100,000 with infantile hydrocephalus being between 1 – 32 per 10,000 births [2]. In all adults the prevalence is about 11:100,000 but when the sample is limited to the elderly population this increases to 175:100,000 and when looking at only those older than 80 years of age, the prevalence is 400:100,000 [2]. It has been found that hydrocephalus is more prevalent in the African and South American populations [2].”

 

Comment 2

There are numerous abbreviations that are not described in the text, beginning from the abstract. Since some abbreviations are of utmost importance in the review, they should be described the first time the appear in the abstract, in the main text and in the figures’ captions. Some of them are: SNARE, SNAP, HYH, CSPa, HSP, PCC MRI, Dgl5(-/-), L1CAM, LKB1, AMPK etc.

Response 2

The full names for the abbreviations have been clarified when they first appeared in the abstract, main text and figure captions and have been highlighted in red. They are as follows:

1. Soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE)
2. Alpha-SNAP: α-soluble NSF attachment protein
3. Hyh: hydrocephalus with hop gait
4. BBB: Blood Brain Barrier
5. ADP: adenosine diphosphate
6. SM proteins: Sec1/Munc18-like proteins
7. NAPA: N-ethylmaleimide-sensitive factor Attachment Protein Alpha
8. LKB1: Liver kinase B1
9. AMPK: Adenosine monophosphate activated protein kinase
10. CD4: Cluster of differentiation 4
11. SNCA: synuclein alpha
12. HSP: Heat shock protein
13. CSPa: Cysteine string protein alpha
14. PCC MRI: posterior cingulate cortex magnetic resonance imaging
15. DLG5: Discs large homolog 5
16. MAGUK: membrane-associated guanylate kinases
17. Munc18: mammalian uncoordinated-18
18. Lgl: lethal giant larvae
19. L1CAM: L1 cell adhesion molecule

 

Comment 3

There is a mistake in figures’ numbering since the first figure has been numbered as figure 2 but there is not figure 1 in the manuscript. And the same problem is shown with the tables since table 2 is missing.

Response 3

The Figures and Tables have been re-numbered and references to them in the text have also been appropriately changed. These are all highlighted in red in the article.

 

Comment 4

Information contained in figure 5 is not legible at all and thus the layout of all the information contained should be presented in other way to make the understanding of what is included in the figure possible. The same problem is present in figure 14.

Response 4

The images have been changed to landscape view to enable them to be enlarged.

Comment 5

Figure 9 contains words that are not English.

Response 5

The image has been re-made with the English translations from Catalan.

 

4. Response to Comments on the Quality of English Language

N/A

 

5. Additional clarifications

None.

 

Please also see the attachement.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

An excellent review about abnormal transcytosis mechanisms in the pathogenesis of hydrocephalus:

• Hydrocephalus is a chronic neurological condition caused by abnormal cerebrospinal fluid (CSF) accumulation, significantly impacting patients' quality of life.
• Its causes remain poorly understood, making neurosurgery the primary treatment.
• Research suggests hydrocephalus may result from impaired macromolecular clearance, leading to increased osmotic load in the ventricles.
• Macromolecules are cleared via processes such as transcytosis, involving caveolae- and clathrin-dependent pathways, SNARE proteins, and vesicular trafficking.
• Abnormalities in transcytosis components, such as mutations in alpha-SNAP and SNARE complexes, disrupt membrane organization and vesicle fusion, potentially contributing to hydrocephalus.
• Other factors, including alpha-synuclein and Rab proteins, may also play roles in vesicle dynamics.
• Insights from animal models, such as hyh mice, highlight the pathological consequences of these disruptions.
• Understanding transcytosis abnormalities in hydrocephalus could lead to novel therapeutic strategies aimed at enhancing macromolecular clearance, reducing ventricular fluid buildup, and improving patient outcomes.

The authors conclude that the process of transcellular transport is complex and has many proteins and factors that regulate it. However, very little research has been done looking at the link between transcellular transport and hydrocephalus formation. Thus, further work in this area can help shed light on the mechanisms behind the formation of hydrocephalus and lead to a better understanding of the disease.

It can also lead to better management strategies for hydrocephalus.

One point left:

I want you to please correct "...help shed a light on..." to "...help shed light on..." in the conclusion.

Congratulations.

Yours sincerely

Author Response

For Review Article: Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Response to Reviewer Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

 

2. Questions for General Evaluation

General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		Many thanks
Is the work well organized and comprehensively described?		Many thanks
Is the work scientifically sound and not misleading?		Many thanks
Are there appropriate and adequate references to related and previous work?		Many thanks
Is the English used correct and readable?	The English is fine and does not require any improvement.	Many thanks

 

3. Point-by-point response to Comments and Suggestions for Authors

Comment 1

I want you to please correct "...help shed a light on..." to "...help shed light on..." in the conclusion.

Response 1

This has been changed to “help shed light on” and has been highlighted in red.

 

4. Response to Comments on the Quality of English Language

N/A

 

5. Additional clarifications

None.

 

Please also see the attachement.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have satisfactorily responded to all the requested changes, and I recommend the acceptance of the manuscript for publication.

Author Response

For Review Article: Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Response to Reviewer Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

 

2. Questions for General Evaluation

General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		Many thanks
Is the work well organized and comprehensively described?		Many thanks
Is the work scientifically sound and not misleading?		Many thanks
Are there appropriate and adequate references to related and previous work?		Many thanks
Is the English used correct and readable?	The English could be improved to more clearly express the research.	Many thanks

 

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1

The authors have satisfactorily responded to all the requested changes, and I recommend the acceptance of the manuscript for publication.

Response 1

Many thanks.

4. Response to Comments on the Quality of English Language

N/A

5. Additional clarifications

None.

Reviewer 2 Report

Comments and Suggestions for Authors

The new version of the manuscript has been much improved, however there are still some items that should be corrected, they are listed bellow:

• Page 8, line 214, "Figure 3 shows the alpha-synuclein has multiple roles", do authors mean Figure 4 or Table 2?
• pages 7-9, lines 203-263, reference [7] is cited 27 times, it could be avoided to insert it between sentences and it could just be included at the end of the paragraph
• character of Figure 5 is still too small
• table 5 and Summary Table are the same? it is confusing

Author Response

For Review Article: Abnormal Transcytosis Mechanisms in the Pathogenesis of Hydrocephalus: A Review

Response to Reviewer Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.

 

2. Questions for General Evaluation

General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		Many thanks
Is the work well organized and comprehensively described?		Many thanks
Is the work scientifically sound and not misleading?		Many thanks
Are there appropriate and adequate references to related and previous work?		Many thanks
Is the English used correct and readable?	The English is fine and does not require any improvement.	Many thanks

 

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1

Page 8, line 214, "Figure 3 shows the alpha-synuclein has multiple roles", do authors mean Figure 4 or Table 2?

Response 1

Changed to Table 2

Comment 2

Pages 7-9, lines 203-263, reference [7] is cited 27 times, it could be avoided to insert it between sentences and it could just be included at the end of the paragraph.

Response 2

Corrected.

Comment 3

Character of Figure 5 is still too small

Response 3

Figure 5 has been made larger.

Comment 4

Table 5 and Summary Table are the same? it is confusing

Response 4

Table 5 is the Summary Table

 

4. Response to Comments on the Quality of English Language

N/A

 

5. Additional clarifications

None.

 

Please also see attached file.