Dysregulation of a Heme Oxygenase–Synuclein Axis in Parkinson Disease
Round 1
Reviewer 1 Report
This review is well organized and collected proper refs. One minor thing to be added in this review is a paragraph related to researches about the HMOX1 functions in PD pathology using genetic models including neuron-specific or brain specific alteration of HMOX1 gene. It would be better to understand astrocyte-specific HMOX1 functions in PD.
Author Response
Answer: The authors would like to thank Reviewer #1 for the comments. With respect to the suggestion to add a paragraph related to different HMOX1 models, we have now added this information on pages 8 and 9 of the manuscript.
Reviewer 2 Report
α-Synuclein is a key pathogenic marker of Parkinson’s disease. HO-1 protein catalyzes the conversion of heme to biliverdin, carbon monoxide, and free ferrous iron. HO-1 is found to be elevated in PD-affected neural tissues and promotes mitochondrial dysfunction, which is also affected by α-Synuclein. This article systematically reviews the link between α-Synuclein, HO-1, miR-153, and miR-223 to PD. The potential of HO-1, miR-153, and miR-223 biomarkers and targets for disease-modifying therapy is also discussed. This review is interesting, however, there are several concerns from me:
- The aim of the review is not clearly stated in the abstract.
- The scope of this review is relatively narrow and seems to mainly discuss the main findings of the authors’ own lab.
- The GFAP.HMOX1 mouse model is the main focus and its related results/studies are widely discussed in this article. However, the authors did not introduce this mouse model. Without reading the reference, we have no idea about the generation and characteristics of the mouse model. In addition, the GFAP.HMOX1 mice do not exhibit Lewy body inclusions even at 19-month old. One of the authors' explanations is that this mouse model “may represent an early-stage model of PD”, which is not so satisfactory, considering that 19-month for mice is quite old already.
- To comprehensively review the role of HMOX1 in PD, the authors should include other in vitro and in vivo models of HMOX1 such as the mutation, knock-down or knockout model, rather than limited to the GFAP.HMOX1 model.
- The mechanisms regarding the link between α-Synuclein, HO-1, miR-153, and miR-223 to PD is not adequately discussed.
Author Response
"α-Synuclein is a key pathogenic marker of Parkinson’s disease. HO-1 protein catalyzes the conversion of heme to biliverdin, carbon monoxide, and free ferrous iron. HO-1 is found to be elevated in PD-affected neural tissues and promotes mitochondrial dysfunction, which is also affected by α-Synuclein. This article systematically reviews the link between α-Synuclein, HO-1, miR-153, and miR-223 to PD. The potential of HO-1, miR-153, and miR-223 biomarkers and targets for disease-modifying therapy is also discussed. This review is interesting, however, there are several concerns from me:"
Answer: The authors would like to thank Reviewer #2 for the constructive comments.
"1. The aim of the review is not clearly stated in the abstract."
Answer: We have added a sentence describing the aim of the review in the Abstract (page 2).
"2. The scope of this review is relatively narrow and seems to mainly discuss the main findings of the authors’ own lab."
Answer: We appreciate this comment, and we have now broadened the scope of the review by including references to other groups studying heme oxygenase-1 as it related to Parkinson’s disease and other disorders. These changes have been made throughout the manuscript.
"3. The GFAP.HMOX1 mouse model is the main focus and its related results/studies are widely discussed in this article. However, the authors did not introduce this mouse model. Without reading the reference, we have no idea about the generation and characteristics of the mouse model. In addition, the GFAP.HMOX1 mice do not exhibit Lewy body inclusions even at 19-month old. One of the authors' explanations is that this mouse model “may represent an early-stage model of PD”, which is not so satisfactory, considering that 19-month for mice is quite old already."
Answer: As per the reviewer’s suggestion, we have now included details describing the development of the GFAP.HMOX1 mouse model (pages 6 and 7).
"4. To comprehensively review the role of HMOX1 in PD, the authors should include other in vitro and in vivo models of HMOX1 such as the mutation, knock-down or knockout model, rather than limited to the GFAP.HMOX1 model."
Answer: We have added a paragraph that provides information on different HMOX1 models.
"5. The mechanisms regarding the link between α-Synuclein, HO-1, miR-153, and miR-223 to PD is not adequately discussed."
Answer: We have additional information to support the link between α-synuclein, HO-1, miR-153 and/or miR-223, as they relate to PD.
Round 2
Reviewer 2 Report
The authors have satisfactorily address reviewers concerns.
