Lobe X of the Cerebellum: A Natural Neuro-Resistant Region
Round 1
Reviewer 1 Report
The authors have extensive experience in cerebellar research and the review is very well structured. The research models used are described and an extensive bibliography is cited, as befits a review of this type. Diagrams and pictures are suitable for non-expert readers to follow the discussion. I believe that there are no significant changes that would improve the review, so I recommend its publication in its current form. Congratulations.
Author Response
We thank the Referee for reading the manuscript and his/her positive opinion about it.
Reviewer 2 Report
This paper summarizes neurodegeneration of the cerebellar cortex mainly in spontaneous mutant models in references to zebrin II/aldolase C-defined cerebellar compartments. Although much information is updated, the paper is somewhat reminiscent of the review article by Sarna and Hawkes (Prog Neurobiol. 70:473-507, 2003) in its structure and contents. I feel the authors are trying to differentiate from the review article by Sarna and Hawkes by focusing on the resistance of neurodegeneration of the lobule X. The paper needs to revise facilitating the reader's understanding and to improve missing of some information.
Point 1. In the section “3. Region of the cerebellar cortex”, the authors explain the cerebellar transverse domains based on the expression pattern of zebrin II/aldolase C. I think the cerebellar transverse domains and the striping patterns of zebrin II/aldolase C and HSP25 in each domain should be illustrated as figure(s) to facilitate the reader's understanding.
Point 2. In the subsection “Tottering, Leaner, and Nagoya Models”, some information is missing. These mutant mice have mutation(s) in a gene coding for α1A subunit of Ca2+ channel (Cav2.1). Pogo mice have been reported as other mutants bearing the Cav2.1 gene mutant, and showed Purkinje cell degeneration (Jeong et al. Dev Brain Res 125:61-67, 2000). In contrast, Purkinje cell loss does not occur in the cerebellum of rolling mice (Nagoya model) (Sawada et al. Congenit Anom 40:99-107, 2000). In aged tottering mice, Purkinje cell degeneration is observed in zebrin II/aldolase C-negative compartments in the anterior vermis and zebrin II/aldolase C-positive compartments in the posterior vermis (Sawada et al. Acta Neurobiol Exp 69:138-145).
Point 3. Sarna et al. (J Comp Neurol 456:279–291, 2003) reported that Purkinje cell degeneration is accompanied by ectopic expression of tyrosine hydroxylase (TH) in zebrin II/aldolase C-positive compartments of the NPC1 model mice. The authors mentioned in the paper that HSP expression may be candidate responsible for resistance to Purkinje cell degeneration in the lobule X. Although HSP25 is expressed in lobules VI and X (Armstrong et al. 434:262-274, 2001), its expression pattern is complementary to ectopic TH expression in the cerebellum of rolling mice (Sawada et al. Brain Res 1343:46-53, 2010). Please expand the Discussion by mentioning not only HSP25 expression but also ectopic TH expression in relevant to the resistance or vulnerability of Purkinje cells in the lobule X.
Author Response
In-text changes corresponding to Reviewer #2 are marked in green
Remarks to the Author:
This paper summarizes neurodegeneration of the cerebellar cortex mainly in spontaneous mutant models in references to zebrin II/aldolase C-defined cerebellar compartments. Although much information is updated, the paper is somewhat reminiscent of the review article by Sarna and Hawkes (Prog Neurobiol. 70:473-507, 2003) in its structure and contents. I feel the authors are trying to differentiate from the review article by Sarna and Hawkes by focusing on the resistance of neurodegeneration of the lobule X. The paper needs to revise facilitating the reader's understanding and to improve missing of some information.
Reply: We agree with the Referee, as the review article of Sarna and Hawkes was really helpful to write our manuscript. However, as the Referee accurately pointed, we want to differentiate from this review by focusing on the resistance of the lobe X, a phenomenon not as described as the neurodegeneration patterns of the cerebellum. Replies to the different questions addressed by the Reviewer will be provided one by one.
Point 1. In the section “3. Region of the cerebellar cortex”, the authors explain the cerebellar transverse domains based on the expression pattern of zebrin II/aldolase C. I think the cerebellar transverse domains and the striping patterns of zebrin II/aldolase C and HSP25 in each domain should be illustrated as figure(s) to facilitate the reader's understanding.
Reply: Effectively, the addition of this figure facilitates the understanding of the manuscript. A schema comparing zebrin II patterns in the four different regions of the cerebellum has been incorporated to the manuscript as the new Figure 4.
Point 2. In the subsection “Tottering, Leaner, and Nagoya Models”, some information is missing. These mutant mice have mutation(s) in a gene coding for α1A subunit of Ca2+ channel (Cav2.1). (1) Pogo mice have been reported as other mutants bearing the Cav2.1 gene mutant, and showed Purkinje cell degeneration (Jeong et al. Dev Brain Res 125:61-67, 2000). (2) In contrast, Purkinje cell loss does not occur in the cerebellum of rolling mice (Nagoya model) (Sawada et al. Congenit Anom 40:99-107, 2000). (3) In aged tottering mice, Purkinje cell degeneration is observed in zebrin II/aldolase C-negative compartments in the anterior vermis and zebrin II/aldolase C-positive compartments in the posterior vermis (Sawada et al. Acta Neurobiol Exp 69:138-145).
Reply: (1) As the Referee pointed, Tottering, Leaner and Nagoya are not the only mutants for α1A subunit of Ca2+ channel gene. A description of all models for this mutation would extend too much the manuscript, and therefore we chose these three examples because they were more described than others. However, Pogo mice is a good addition to the manuscript list. Thanks to the Referee’s advice and the reference provided, we have included information about Pogo degeneration, which, moreover, supports our work: the posterior lobes suffer less degeneration than the anterior ones at P120 (Jeong et al., 2000, page 66).
(2) Regarding the Purkinje cell death that does not occur in the Nagoya mouse, we have applicated this correction with the citation kindly provided by the Referee.
(3) We want to thank to the Referee for this worthy information. It has been included in the subsection with the reference provided. Additionally, these striking data are really helpful to discuss that Zebrin II does not present full neuroprotective properties.
Point 3. Sarna et al. (J Comp Neurol 456:279–291, 2003) reported that Purkinje cell degeneration is accompanied by ectopic expression of tyrosine hydroxylase (TH) in zebrin II/aldolase C-positive compartments of the NPC1 model mice. The authors mentioned in the paper that HSP expression may be candidate responsible for resistance to Purkinje cell degeneration in the lobule X. Although HSP25 is expressed in lobules VI and X (Armstrong et al. 434:262-274, 2001), its expression pattern is complementary to ectopic TH expression in the cerebellum of rolling mice (Sawada et al. Brain Res 1343:46-53, 2010). Please expand the Discussion by mentioning not only HSP25 expression but also ectopic TH expression in relevant to the resistance or vulnerability of Purkinje cells in the lobule X.
Reply: This information has been updated in their corresponding parts. We thank the Referee for his/her precise corrections. Moreover, the references given have allowed us to improve the manuscript much easier, and we are grateful for that. Without any doubt, the manuscript quality has improved after all the modifications.
Reviewer 3 Report
This is an interesting review/work highlighting the involvement of cerebellum in neurodegeneration.
Please include the objective of this review and gap of study that leads to inception of the review.
It is worth mentioning that 3-AP, 3-acetylpyridine can cause damage to the inferior olivary nucleus
It is advisable to rearrange the citations in the following statement by chronological order:
We have found that lobe X of the cerebellum is more resistant than the other lobes in numerous animal models suffering Purkinje cell death. As described above, some examples are the Leaner (Heckroth and Abbott, 1994), Toppler (Duchala et al., 2004), Robotic (Isaacs et al., 2003), Shaker (Tolbert et al., 1995), Lurcher (Duffin et al., 2010), NPC1 (Praggastis et al., 2015), and PCD (Mullen et al., 1976) models.
Please prepare some Tables to capture the information in section 4: Models of Cerebellar Degeneration
Author Response
In-text changes corresponding to Reviewer #3 are marked in blue
Remarks to the Author:
This is an interesting review/work highlighting the involvement of cerebellum in neurodegeneration.
Reply: We are pleased that the manuscript has resulted interesting for the Referee.
Please include the objective of this review and gap of study that leads to inception of the review.
Reply: This information can help our review to be distinguished from other articles. It has been included in the abstract to attract readers attention, and a new section “2. Objective” has been created to make clear this statement.
It is worth mentioning that 3-AP, 3-acetylpyridine can cause damage to the inferior olivary nucleus
Reply: We have added 3-acetylpyridine in the subsection “Other Non-genetic Models”. Unluckily, there is no data of this interesting chemical over lobe X
It is advisable to rearrange the citations in the following statement by chronological order:
We have found that lobe X of the cerebellum is more resistant than the other lobes in numerous animal models suffering Purkinje cell death. As described above, some examples are the Leaner (Heckroth and Abbott, 1994), Toppler (Duchala et al., 2004), Robotic (Isaacs et al., 2003), Shaker (Tolbert et al., 1995), Lurcher (Duffin et al., 2010), NPC1 (Praggastis et al., 2015), and PCD (Mullen et al., 1976) models.
Reply: The order of the citations has been rearranged according to this suggestion.
Please prepare some Tables to capture the information in section 4: Models of Cerebellar Degeneration
Reply: A table is an excellent recommendation to summarize the information of the models described here. It has been added at the end of the section Models of Cerebellar Degeneration.
Round 2
Reviewer 2 Report
The manuscript was appropriately corrected.
