The Role of DNA in Neural Development and Cognitive Function
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe article by Tharsius Raja and colleagues provides details of the Role of DNA in Neural Development and Cognitive Function. In this review article, the authors explored genetic and epigenetic processes in neurodevelopment and DNA damage/repair mechanisms related to multiple NDs. Overall, this well-written article provides the fundamental role of DNA in coordinating the intricate interactions between molecular and environmental factors. The overall quality of the article can be improved, and the following changes are needed.
The introduction section can be improved with more background literature on the neurodevelopmental part.
Section 2. The role of Genes in Brain Formation needs further improvement by discussing the role of genes in detail. Similarly, Table 1 can be improved.
The authors have only focused on Alzheimer's disease in depth. While the review article mentions PD and ALS, it does not cover them sufficiently. The authors must include Figures for PD and ALS.
The following changes can be made in the Figures.
- In Figure 1, some of the text is not visible. The authors can increase the font sizes for better readability.
- The text should be written in free spaces and not on the Figure component.
- The text should be uniform in size in the Figure.
- The arrows should be used to highlight a particular location within the figure.
- In Figure 2, the text looks like it is stretched, and it can be corrected with the same font throughout the Figure.
- Aβ should be mentioned in Alzheimer's neurons.
- “Agregation” should be replaced by “Aggregation”
- The figure legends would benefit from additional detail for the Figures. More comprehensive explanations of each figure's content, mechanistic approach, etc., will benefit the reader's interest. The legend for Figure 3 must be improved.
Author Response
Response to Reviewer 1 Comments
Thank you very much for taking the time to review this manuscript. Please find detailed responses below and the revisions/corrections highlighted/in track changes in the re-submitted files.
Point-by-point response to Comments
Comments: The introduction section can be improved with more background literature on the neurodevelopmental part.
Response: We express our gratitude for the constructive feedback provided by the reviewer. The introduction has undergone substantial revision to incorporate a more extensive array of background literature about neurodevelopmental stages, encompassing the significance of neural progenitor identity, synaptogenesis, and critical periods of development. Essential references [1–10] have been integrated to encapsulate contemporary findings and theoretical perspectives regarding the neurodevelopmental mechanisms underpinning cognitive function and the brain's architecture.
Comments: Section 2. The role of Genes in Brain Formation needs further improvement by discussing the role of genes in detail. Similarly, Table 1 can be improved.
Response: We appreciate the insightful comments offered. Section 2 has been augmented to encompass a more thorough examination of pivotal genes implicated in brain patterning (e.g., Otx1/2, Mash1, Neurogenins), as well as their roles in neural progenitor commitment and subtype specification. Additionally, we have elaborated on their temporal and spatial expression patterns and the regulatory interactions that occur during the process of neurogenesis. Moreover, the contributions of BDNF, COMT, and APOE have been discussed in greater depth, establishing connections between their expression profiles and functional neurodevelopment and neurodegenerative disorders.
Table 1 has been meticulously reformatted to enhance clarity and has been supplemented with additional gene-function relationships. We have also revised the headings of the table and incorporated more descriptive elucidations of gene functions, particularly about synaptic plasticity and subtype differentiation.
Comments: The authors have only focused on Alzheimer's disease in depth. While the review article mentions PD and ALS, it does not cover them sufficiently. The authors must include Figures for PD and ALS.
Response: We recognize this disparity and have taken steps to rectify it by significantly expanding the sections dedicated to Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). We have introduced two new figures: Figure 4 for PD and Figure 5 for ALS, which elucidate the key molecular mechanisms, gene mutations, and pathological processes associated with each respective disease.
The following changes can be made in the Figures.
Comments: In Figure 1, some of the text is not visible. The authors can increase the font sizes for better readability.
Response: As per the reviewer’s comment, Figure 1 is improved.
Comments: The text should be written in free spaces and not on the Figure component.
Response: As per the reviewer's comment, corrected.
Comments: The text should be uniform in size in the Figure.
Response: corrected.
Comments: The arrows should be used to highlight a particular location within the figure.
Response: As per the reviewer’s comment, we have revised Figure 1 to enhance readability by increasing font size, ensuring consistency across text size, and relocating all labels to vacant spaces outside the primary components of the figure for improved clarity. The important location is highlighted.
Comments: In Figure 2, the text looks like it is stretched, and it can be corrected with the same font throughout the Figure.
Response: Corrected.
Comments: Aβ should be mentioned in Alzheimer's neurons.
Response: Corrected.
Comments: “Agregation” should be replaced by “Aggregation”
Response: Corrected.
Comments: The figure legends would benefit from additional detail for the Figures. More comprehensive explanations of each figure's content, mechanistic approach, etc., will benefit the reader's interest. The legend for Figure 3 must be improved.
Response: All figure legends have been meticulously revised to provide enhanced mechanistic detail. The legend for Figure 3 now delineates the process of ROS-induced DNA damage, the feedback mechanisms involving mitochondria, and the critical role of DNA repair systems in the maintenance of cognitive function.
Author Response File: 
Author Response.doc
Reviewer 2 Report
Comments and Suggestions for AuthorsThe neurodegenerative disorders are a huge problem in the current civilisation. It can be expected that environmental pollution, highly processed food and lack of physical activity cause to neuronal conditions. Moreover, the second point is that the neurons are not replicated cells. Therefore, their numbers are constant or, in some cases, can be reduced. Alcohol consumption, tobacco smoking, and degenerative products of lipids are only example of harmful factors which leads to the neurons reduction. Additionally, the speed of life and permanent stress with the high level of cortisol can cause a reduction of the proper neuron condition (level of oxygen). Obesity and diabetes can lead to stroke and, therefore, brain mass reduction.
Additionally, in neuron cells, only the sense strand is under repair – the authors did not discuss this problem.
Authors also put their attention only on the genetic material and almost nothing on the nutritional problems.
The BER is not only one system which maintains the DNA damage, the second one, and also very important is NER, which can remove such lesions as T^T or cdPu.
From the editorial point of view, the article is well written and readable, with correctly cited references.
Even to the above, I have found the educational potential in this article.
In conclusion, I cannot recommend the manuscript for publication in its present form, but I believe that the authors will make an effort to correct it.
Author Response
Response to Reviewer 2 Comments
Thank you very much for taking the time to review this manuscript. Please find detailed responses below and the revisions/corrections highlighted/in track changes in the re-submitted files.
Point-by-point response to Comments
Comments: Neurodegenerative disorders are a huge problem in the current civilisation. It can be expected that environmental pollution, highly processed food and lack of physical activity cause to neuronal conditions.
Response: We value the reviewer's perceptive observation. In response, we have added more information to the manuscript's introduction and discussion sections to emphasize the growing body of research that links the rising incidence of neurodegenerative diseases to dietary practices, environmental pollution, and sedentary lifestyles, especially the overconsumption of highly processed foods. These elements are now covered together with pertinent references to current research that demonstrates the link between lifestyle and environmental factors and neuronal health.
Comments: Moreover, the second point is that the neurons are not replicated cells. Therefore, their numbers are constant or, in some cases, can be reduced. Alcohol consumption, tobacco smoking, and degenerative products of lipids are only example of harmful factors which leads to the neurons reduction.
Response: We appreciate the reviewer's insightful feedback. As indicated, we have discussed in detail how neurons have a limited potential for regeneration and how unhealthy lifestyle choices like smoking, drinking, and reactive lipid metabolites affect the vitality of neurons. The updated paper now places more emphasis on this point, with important references addressing neuronal loss and susceptibility as a result of these harmful influences.
Comments: Additionally, the speed of life and permanent stress with a high level of cortisol can cause a reduction of the proper neuron condition (level of oxygen).
Response: We value the reviewer's emphasis on the connection between cortisol and ongoing stress. A detailed explanation of how long-term psychological stress and high cortisol levels might impair brain neuronal activity and oxygen metabolism has been added to the paper. This contribution supports the manuscript's emphasis on physiological and environmental factors and serves to highlight the complex nature of neurodegenerative diseases.
Comments: Obesity and diabetes can lead to stroke and, therefore, brain mass reduction.
Response: We appreciate your insightful perspective. We concur that diabetes and obesity are known risk factors for stroke, which can lead to a decrease in brain mass. To present a more thorough view of the systemic impacts of metabolic diseases on brain health, we have now acknowledged this link in the discussion section of the updated text.
Comments: Additionally, in neuron cells, only the sense strand is under repair – the authors did not discuss this problem.
Response: We value the reviewer's attention to this crucial mechanical aspect. A key factor in comprehending the genomic stability of neurons is the preferential repair of the sense strand in neuron cells. Although strand-specific repair mechanisms were not the primary focus of our current investigation, we have now addressed this topic briefly in the amended text, along with the relevant references. The reader's comprehension of potential drawbacks and underlying biological mechanisms pertinent to our findings is improved by this inclusion.
Comments: Authors also put their attention only on the genetic material and almost nothing on the nutritional problems.
Response: In response to this critique, we have broadened the discussion in Section 3 to encompass the effects of nutritional deficiencies (including iron, zinc, copper, LC-PUFAs, folate, etc.) on myelination, neurotransmitter production, and cognitive advancement. This enhancement effectively bridges the nexus between epigenetic modification and the role of diet during neurodevelopment.
Comments: The BER is not only one system which maintains the DNA damage, the second one, and also very important is NER, which can remove such lesions as T^T or cdPu. From the editorial point of view, the article is well written and readable, with correctly cited references. Even to the above, I have found the educational potential in this article.
Response: We have now incorporated an extensive elucidation of the nucleotide excision repair (NER) pathway, emphasizing its critical function in rectifying UV-induced and oxidative DNA lesions such as thymine dimers and cyclic pyrimidine dimers (cdPu). Additionally, we have included a discussion on the synergistic relationship between BER and NER, particularly concerning the maintenance of mitochondrial DNA under oxidative stress conditions (Section 4).
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsAccept
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors correctly answered my question and provided a reasonable amount of new information to the article. Therefore, I can recommend this text for publication
