Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

Round 1

Reviewer 1 Report

Significant plagiarism was found in this review manuscript, with sentences copied from two recent reviews on MSA and PSP separately, “Katzeff JS, Phan K, Purushothuman S, Halliday GM, Kim WS. Cross-examining candidate genes implicated in multiple system atrophy. Acta Neuropathol Commun. 2019 Jul 24;7(1):117” and “Wen Y, Zhou Y, Jiao B, Shen L. Genetics of Progressive Supranuclear Palsy: A Review. J Parkinsons Dis. 2021;11(1):93-105”, respectively. I have here highlighted only a few of the instances below.

 

1.      Page 2 line 66: “Mutations in SNCA (A30P, E46K, H50Q, G51D and A53T) are known to cause PD. However, no causal relationship between SNCA mutations for MSA exists to date, and the association between variant α-synuclein and MSA is still debatable” vs “Mutations in SNCA (A30P, E46K, H50Q, G51D and A53T) are known to cause PD. However, no causal SNCA mutations for MSA have been found to date, and the association between variant α-synuclein and MSA is still unproven” in Katzeff et al. 2019 (p2);

2.      Page 2 line 72: “These findings suggest that G51D could be relevant to MSA as well as PD, although it has not been found in cases with only MSA pathology. Similarly, a Finnish family with SNCA A53E variant showed neuropathological hallmarks of both MSA and PD” Vs “These findings suggest that G51D could be relevant to MSA as well as PD, although it has not been found in cases with only MSA pathology. Similarly, a Finnish family with SNCA A53E variant showed neuropathological hallmarks of both MSA and PD” in Katzeff et al. 2019 (p2);

3.      Page 3 line 95: “The pathological relationship between COQ2 and MSA was reinforced when it was discovered that plasma coenzyme Q10 levels were lower in MSA patients compared to healthy controls” vs “The pathological link between COQ2 and MSA was strengthened when it was discovered that plasma coenzyme Q10 levels were lower in MSA patients compared to healthy controls” in Katzeff et al. 2019 (p2);

4.      Page 3 line 102: “Furthermore, coenzyme Q10 levels were found to be lower in the cerebellum, along with increases in mitochondrial dysfunction and oxidative stress, in MSA cases compared to controls” vs “Furthermore, coenzyme Q10 levels were found to be lower in the cerebellum, along with increases in mitochondrial dysfunction and oxidative stress, in MSA cases compared to controls” in Katzeff et al. 2019 (p2);

5.      Page 6 line 29: “The frequency of PSP cases carrying MAPT mutations is various with a range from 0.6% to 14.3%. In total, 15 different mutations of MAPT have been described in cases with PSP clinical or neuropathological diagnosis, as shown in Table 2…” vs “The frequency of PSP cases carrying MAPT mutations is various with a range from 0.6% to 14.3%. In total, 15 different mutations of MAPT have been described in cases presenting as PSP (clinical or neuropathological diagnosis) as shown in Table 1…” in Wen et al. 2021 (p3). The two Tables were also of the same order in the list of studies and of significant similarity.

6.      Page 9 line 6: “The onset of PSP is insidious…” vs “The onset of PSP is insidious…” in Wen et al. 2021 (p3);

7.      Page 11 line 15: “Therefore, the LRRK2 gene is a rare pathologic gene associated with PSP despite inconsistent results in some studies. More association studies in larger cohorts and various populations are needed to further elucidate how these LRRK2 mutations lead to tauopathy and whether other mutations increase the risk for PSP.” Vs “Therefore, we conclude that the LRRK2 gene is a rare pathologic gene associated with PSP despite inconsistent results in some studies. More association studies in larger cohorts and various populations are needed to further elucidate how these LRRK2 mutations lead to tauopathy and whether other mutations increase the risk for PSP” in Wen et al. 2021 (p5).

Author Response

Comments and Suggestions for Authors

Reviewer 1

Significant plagiarism was found in this review manuscript, with sentences copied from two recent reviews on MSA and PSP separately, “Katzeff JS, Phan K, Purushothuman S, Halliday GM, Kim WS. Cross-examining candidate genes implicated in multiple system atrophy. ActaNeuropatholCommun. 2019 Jul 24;7(1):117” and “Wen Y, Zhou Y, Jiao B, Shen L. Genetics of Progressive Supranuclear Palsy: A Review. J Parkinsons Dis. 2021;11(1):93-105”, respectively. I have here highlighted only a few of the instances below.

OUR RESPONSE: All the manuscript has been extensively edited in order to reduce the repletion rate

1. Page 2 line 66: “Mutations in SNCA (A30P, E46K, H50Q, G51D and A53T) are known to cause PD. However, no causal relationship between SNCA mutations for MSA exists to date, and the association between variant α-synuclein and MSA is still debatable” vs “Mutations in SNCA (A30P, E46K, H50Q, G51D and A53T) are known to cause PD. However, no causal SNCA mutations for MSA have been found to date, and the association between variant α-synuclein and MSA is still unproven” in Katzeff et al. 2019 (p2);

OUR RESPONSE: Just not to find similarity please find the sentence modified as:’’Mutations in SNCA (A30P, E46K, H50Q, G51D and A53T) have been identified to be associated with are known to cause PD [18].However, causality was not revealed between SNCA mutations for and MSA to date, and the association relationship between variant α-synuclein and MSA is still unverifieddebatable.’’ (lines 17-20 page 4)

 

2. Page 2 line 72: “These findings suggest that G51D could be relevant to MSA as well as PD, although it has not been found in cases with only MSA pathology. Similarly, a Finnish family with SNCA A53E variant showed neuropathological hallmarks of both MSA and PD” Vs “These findings suggest that G51D could be relevant to MSA as well as PD, although it has not been found in cases with only MSA pathology. Similarly, a Finnish family with SNCA A53E variant showed neuropathological hallmarks of both MSA and PD” in Katzeff et al. 2019 (p2); OUR RESPONSE: Just not to find similarity please find the sentence modified as:’’Even though G51D was not confirmed in cases with only autopsy proven pathology, it may be linked both with MSA and PD. These findings suggest that G51D could be relevant to MSA as well as PD, although it has not been found in cases with only MSA pathology. Equivalently Similarly, members of Finnish family with SNCA A53E variant shared showed typical neuropathological hallmarks signatures of both MSA and PD.’’ (lines 24-28 page 4)

 

3. Page 3 line 95: “The pathological relationship between COQ2 and MSA was reinforced when it was discovered that plasma coenzyme Q10 levels were lower in MSA patients compared to healthy controls” vs “The pathological link between COQ2 and MSA was strengthened when it was discovered that plasma coenzyme Q10 levels were lower in MSA patients compared to healthy controls” in Katzeff et al. 2019 (p2);

 OUR RESPONSE: Just not to find similarity please find the sentence modified as:’’  The pathological relationship between COQ2 and MSA was reinforced when it was discovered that Reduced plasma coenzyme Q₁₀ levels were lower in MSA patients compared to healthy controls support further a pathogenetic role of  COQ2 in MSA (lines 12-13 page 5)

 

4. Page 3 line 102: “Furthermore, coenzyme Q10 levels were found to be lower in the cerebellum, along with increases in mitochondrial dysfunction and oxidative stress, in MSA cases compared to controls” vs “Furthermore, coenzyme Q10 levels were found to be lower in the cerebellum, along with increases in mitochondrial dysfunction and oxidative stress, in MSA cases compared to controls” in Katzeff et al. 2019 (p2);

 OUR RESPONSE: Just not to find similarity please find the sentence modified as: ‘’Moreover Furthermore, lower coenzyme Q₁₀ levels were found to be lower in the cerebellum, were associated with elevated mitochondrial dysfunction and oxidative stress, in the cerebellum of postmortem MSA cases compared to controls [41]’’.(lines 20-22 page5)

 

5. Page 6 line 29: “The frequency of PSP cases carrying MAPT mutations is various with a range from 0.6% to 14.3%. In total, 15 different mutations of MAPT have been described in cases with PSP clinical or neuropathological diagnosis, as shown in Table 2…” vs “The frequency of PSP cases carrying MAPT mutations is various with a range from 0.6% to 14.3%. In total, 15 different mutations of MAPT have been described in cases presenting as PSP (clinical or neuropathological diagnosis) as shown in Table 1…” in Wen et al. 2021 (p3). The two Tables were also of the same order in the list of studies and of significant similarity.

 

OUR RESPONSE: Just not to find similarity please find the sentence modified as:’’PSP patients with MAPT mutations cover a wide range of frequencies between 0.6% to 14.3% The frequency of PSP cases carrying MAPT mutations is various with a range from 0.6% to 14.3%’’ .(lines 8-9 page 11) The two Tables were also were modified accordingly.

 

6. Page 9 line 6: “The onset of PSP is insidious…” vs “The onset of PSP is insidious…” in Wen et al. 2021 (p3);

OUR RESPONSE: Just not to find similarity please find the sentence modified as:’’Τhe onset symptoms of PSP are less clear-cut’’.(line 6 page 11)

 

7. Page 11 line 15: “Therefore, the LRRK2 gene is a rare pathologic gene associated with PSP despite inconsistent results in some studies. More association studies in larger cohorts and various populations are needed to further elucidate how these LRRK2 mutations lead to tauopathy and whether other mutations increase the risk for PSP.” Vs “Therefore, we conclude that the LRRK2 gene is a rare pathologic gene associated with PSP despite inconsistent results in some studies. More association studies in larger cohorts and various populations are needed to further elucidate how these LRRK2 mutations lead to tauopathy and whether other mutations increase the risk for PSP” in Wen et al. 2021 (p5).

 OUR RESPONSE: Just not to find similarity please find the sentence modified as:’’Therefore, the LRRK2 gene is a rare pathologic gene associated with PSP despite inconsistent results in some studies. More association studies in larger cohorts and various populations are needed warrant to further elucidate explore the LRRK2 mutations mechanisms related lead to tauopathy and whether other mutations increase the high PSP risk could be explained by novel mutations. ’’.(lines 19-23 page 14)

 

Author Response File: Author Response.docx

Reviewer 2 Report

Review by Anastasia Bougea describe the genetic mutations behind MSA and PSP, two distinct Parkinsonian disorders. The topic is interesting considering that both disorders are usually not associated with genetic mutations. 

Still there are few drawbacks that need to be addressed before the manuscript can be published.

In introduction it is stated that following mutation will be discussed SNCA, COQ2, MAPT, GBA1, LRRK2, DCTN1, NPC1, PARK2, TARDBP, GRN, TBK1 and C9orf72. At the same time only some of the terms where used in screening of literature (“Progressive supranuclear palsy’’, ‘’Multiple System atrophy’’, GBA1 ‘’COQ2’’, ‘’MAPT’’, ‘’SNCA’’,‘’LRRK2’’, ‘’DCTN1’’ , ‘’ GWAS’’). This should be clarified, since it seems that some search results can be missed.

Why only MEDLINE databases were used?

It is strange to discuss only MSA and PSP. CBS/CBD is connected much more to PSP than MSA and should be also included.

As stated before, MSA and PSP are rarely connected with genetic mutations. therefore, some discussion should be presented giving the percentage of genetic vs idiopathic MSA and PSP.

Also, since MSA an PSP, as well as PD, CBD, LBD and other disorders are usually connected with copathologies, it should be stated if any of the discussed studies taken into account occurrence of copathologies.

Similarly, was it taken into account that the disorders presented in the study can be only confirmed postmortem? And any genetic analysis on material taken from living patient can be misdiagnosed. It is especially important for CBD and PSP pathology. 

Text should be corrected for some missing/double spaces and minor spelling mistakes.

 

Author Response

Comments and Suggestions for Authors

Reviewer2

Review by Anastasia Bougea describe the genetic mutations behind MSA and PSP, two distinct Parkinsonian disorders. The topic is interesting considering that both disorders are usually not associated with genetic mutations. 

Still there are few drawbacks that need to be addressed before the manuscript can be published.

In introduction it is stated that following mutation will be discussed SNCA, COQ2, MAPT, GBA1, LRRK2, DCTN1, NPC1, PARK2, TARDBP, GRN, TBK1 and C9orf72. At the same time only some of the terms where used in screening of literature (“Progressive supranuclear palsy’’, ‘’Multiple System atrophy’’, GBA1 ‘’COQ2’’, ‘’MAPT’’, ‘’SNCA’’,‘’LRRK2’’, ‘’DCTN1’’ , ‘’ GWAS’’). This should be clarified, since it seems that some search results can be missed.

OUR RESPONSE: I corrected it:’’The search was conducted between March 2022 and August 2022. We used the terms “Progressive supranuclear palsy’’, ‘’Multiple System atrophy’’, GBA1 ‘’COQ2’’, ‘’MAPT’’, ‘’SNCA’’,‘’LRRK2’’, ‘’DCTN1’’ , ‘’NPC1’’  , ‘’PARK2’’, ‘’TARDBP’’, ‘’GRN’’, ‘’TBK1’’, ‘’C9orf72 ‘’ (line1 page 17)

Why only MEDLINE databases were used?

OUR RESPONSE: Isearched the PubMed/MEDLINE databases but we ensured that all available bibliography was included. The literature was updated to comprise the latest evidence; limits of inclusion and exclusion criteria were defined for study selection.

It is strange to discuss only MSA and PSP. CBS/CBD is connected much more to PSP than MSA and should be also included.

OUR RESPONSE: MSA and PSP are the most common causes of neurodegenerative-parkinsonism, after PD. PSP is the second most common parkinsonian syndrome of neurodegenerative onset, after sporadic PD. I focused only on them as the common representatives of synucleinopathies and taupathies and as the most common  atypical parkinsonian syndromes . PSP and MSA are also commonly mistaken for one another in clinical practice.

As stated before, MSA and PSP are rarely connected with genetic mutations. therefore, some discussion should be presented giving the percentage of genetic vs idiopathic MSA and PSP.

OUR RESPONSE: ‘’The prevalence of  MSA was estimated at 3.4-4.9 cases per 100,000 and the average incidence at 0.6-0.7 cases per 100,000 person-years. PSP is a debilitating tauopathy with an estimated annual prevalence of 5–7 per 100,000 persons and an annual incidence between 0.9 and 2.6 per 100,000 persons (lines page)……. In a large retrospective study of 375 pathologically confirmed PSP cases, excluding those carrying a MAPT mutation, 18,2 %  was sporadic PSP cases, whereas family history of PSP, parkinsonism or dementia was observed in 15% of the cases’’ (lines page)

Also, since MSA an PSP, as well as PD, CBD, LBD and other disorders are usually connected with copathologies, it should be stated if any of the discussed studies taken into account occurrence of copathologies.

OUR RESPONSE: Just to clarify: the reason that I used the term ‘’Neuropathologic diagnosis’’ format of all tables 1,2 and 3 was  to highlight the occurrence of copathologies .  For example in Table 2. MAPT mutations causing PSP-like syndrome, Fujioka et al reported that the clinical diagnosis of their sample was PSP but the neuropathologic diagnosis of PSP with concomitant AD. However as it is obvious from the table 2 , in other studies there are no available data of the copathologies. Thus, I stated in the limitation part of the discussion the lack of the  available data of the copathologies in the included studies. (line24 page 16)

Similarly, was it taken into account that the disorders presented in the study can be only confirmed postmortem? And any genetic analysis on material taken from living patient can be misdiagnosed. It is especially important for CBD and PSP pathology. 

OUR RESPONSE:  Throughout the manuscript it is clearly stated in several parts that:’’ In a large retrospective study of 375 pathologically confirmed PSP cases, excluding those carrying a MAPT mutation…’’, ‘’ Even though G51D was not confirmed in cases with only autopsy proven pathology, …’’, ‘’In another study consisting of 127 pathologically-confirmed cases of MSA, H2 and H1E were associated with decreased risk of MSA…’’ , ‘’lower coenzyme Q₁₀ levels were found to be lower in the cerebellum, were associated with elevated mitochondrial dysfunction and oxidative stress, in the cerebellum of postmortem MSA cases compared to controls [38].’’

 

Text should be corrected for some missing/double spaces and minor spelling mistakes.

OUR RESPONSE: The manuscript was corrected for missing/double spaces and minor spelling errors.

 

 

Author Response File: Author Response.docx

Reviewer 3 Report

This manuscript covers an interesting topic, Genetics of Multiple system atrophy and Progressive supranuclear palsy: A systemised review of the literature. Overall, the manuscript has some strengths, but also various weaknesses, as outlined below. I have suggestions below as to how the manuscript could be improved.

1.     The author needs to make an adequate case background for this review article, as in recent years many similar review articles have been published. The authors should cite and briefly discuss recent relevant review articles in the introduction.

2.     Some of the sections do not appear to show a balanced description of the literature at hand, as the source of the discussed data is not put into context. Here mainly case studies are described, which are interesting but the limitations of these in terms of extrapolating to all MSA and PSP cases should be clearly stated.

3.     Though author aim was not to perform the a systematic review and meta-analysis but the study design was very weak. Inclusion/exclusion criteria was not clearly defined. It will good if author present a flow diagram for study design which include the various steps of study design, including the inclusion criteria, number of studies found in initial stage, then number of study included in final stage etc.

4.     Also, in inclusion criteria author mentioned that included human studies, animal, and cell culture studies but it is not always clear whether the studies being discussed were carried out in cell culture, mice/rodents or humans (e.g. Although tau is present in GCI [40]). Please clarify where necessary.

5.     A large number of original references are missing here (e.g. PMID: 19538213), and the studies mentioned are also not exhaustive, as only 3-4 studies are mentioned here.

6.     Its difficult to identify that information was taken from review article or from research articles (original references). Please clarify where necessary.

7.     Some of the sections do not appear to depict the entirety of the literature and thus it appears like the authors selected particular studies and omitted others to suit their narrative. The discussion should instead be more nuanced and include studies reporting negative or divergent results as well.

8.     It appreciates that Author presented few tables for the selected genes in the manuscript. However, manuscript would benefit greatly if one table summarizing all of the published relevant gene findings. One approach could be a table on preclinical (mainly rodent) studies, and one on cell culture and a separate table on clinical/human studies.

9.     The discussion should be more elaborative.

1.  It would be good if author can focus and presented some data on sex/gender stratified basis.

1.  Ensure abbreviations are always defined at the first mention in text – this is not always the case (e.g. PSP-P, line 37 and other instances).

1.  Some common errors were observed like no gap between the words and reference cited.

Author Response

Comments and Suggestions for Authors

Reviewer  3

This manuscript covers an interesting topic, Genetics of Multiple system atrophy and Progressive supranuclear palsy: A systemised review of the literature. Overall, the manuscript has some strengths, but also various weaknesses, as outlined below. I have suggestions below as to how the manuscript could be improved.

1. The author needs to make an adequate case background for this review article, as in recent years many similar review articles have been published. The authors should cite and briefly discuss recent relevant review articles in the introduction.

OUR RESPONSE: I comment about the previous reviews : ‘’ Previous review  concluded that there no susceptibility genes of MSA [18]. By contrast, other review suggested that certain genes play a role in the susceptibility to PSP pathology (such as MAPT) [19].’’ (lines 26-27 page 2)

 

 

2. Some of the sections do not appear to show a balanced description of the literature at hand, as the source of the discussed data is not put into context. Here mainly case studies are described, which are interesting but the limitations of these in terms of extrapolating to all MSA and PSP cases should be clearly stated.

 OUR RESPONSE: The aim of the present review was to discuss critically  genetic studies on MSA and PSP. By searching the bibliography, these studies were identified as case studies. Indeed, the limitations of their design nature in terms of extrapolating to all MSA and PSP cases was discussed in the discussion; ‘’ . Indeed, case studies were mainly performed, which are interesting but there are significant limitations of these in terms of extrapolating to all MSA and PSP cases [63-69, 92-100]. ‘’ (lines 24-26 page 16 )

 

3. Though author aim was not to perform the a systematic review and meta-analysis but the study design was very weak. Inclusion/exclusion criteria was not clearly defined. It will good if author present a flow diagram for study design which include the various steps of study design, including the inclusion criteria, number of studies found in initial stage, then number of study included in final stage etc.

 OUR RESPONSE: This is a narrative systemized review  as previously described [Grant, M.;Booth, A. A typology of reviews: An analysis of 14 review types and associated methodologies. Health Info Libr J 2009, 26, 91–108]. I also present the flowchart of the study selection in the Result part: ‘’ in From 1.166 studies, after removing 833 duplicates, 132 reports were eligible for review according to the inclusion criteria. Finally, after full text review, 43 studies concerning PSP and MSA mutations were selected for analysis; the Figure1 presents the flowchart of the study selection.’’

 

4. Also, in inclusion criteria author mentioned that included human studies, animal, and cell culture studies but it is not always clear whether the studies being discussed were carried out in cell culture, mice/rodents or humans (e.g. Although tau is present in GCI [40]). Please clarify where necessary.

OUR RESPONSE: I clarify  when included human studies as:’’ In another study of 127 pathologically-confirmed cases of MSA, H2 and H1E were correlated with decreased risk of MSA, whereas H1x and H1J were correlated with increased risk of MSA [45].’’…’’ However, in a study of 108 neuropathologically- confirmed MSA cases, no link was found between GBA1 mutations and MSA [49]. Moreover, the GBA1 L444P mutation was not correlated with MSA in 54 Chinese MSA patients [50]. Additionally no causal link was proven with 54 lysosomal storage disorder genes in 375 MSA patients [51]. Importantly, GBA mutations do not  appear to  be involved in the predisposition to 167 MSA autopsy- proven series ’’

 

Or cell- culture (in vitro studies): Despite the presence of tau in GCI [41], it is debated if tau could be involved in MSA pathogenesis or whether this develop later in the disease process.’’

 

 

Or animal mice/rodents: ‘’ Moreover, functional in vitro studies have demonstrated that the G2019S mutation increases kinase activity, potentially explaining the presence of tau or a-synuclein, through enhanced phosphorylation [101].’’

 

5. A large number of original references are missing here (e.g. PMID: 19538213), and the studies mentioned are also not exhaustive, as only 3-4 studies are mentioned here.

 OUR RESPONSE: The aim of this review was to  discuss briefly  and critically the genes that are potentially linked with MSA – SNCA, COQ2, MAPT, GBA1, LRRK2 and C9orf72 – and those associated with PSP- MAPT, LRRK2, DCTN1, NPC1, PARK2, TARDBP, GRNTBK1 and C9orf72, highlight the overlapped genetic areas of MSA and PSP, and discuss future directions. Some more important papers were added: Madzar D, Schulte C, Gasser T. Screening for LRRK2 R1441 mutations in a cohort of PSP patients from Germany. Eur J Neurol. 2009 Nov;16(11):1230-2. Katzeff, J.S, Phan, K., Purushothuman, S., Halliday, G.M., Kim, W.S. Cross-examining candidate genes implicated in multiple system atrophy. Acta Neuropathol Commun. 2019, 7(1), 117. Stefanova N, Reindl M, Poewe W, Wenning GK. In vitro models of multiple system atrophy. Mov Disord. 2005 ;20 Suppl 12:S53-6.  (see refs)

 

6. Its difficult to identify that information was taken from review article or from research articles (original references). Please clarify where necessary.

OUR RESPONSE: I clarify if the data were taken from review:’’ Previous reviews have concluded that there no susceptibility genes of MSA [18]. By contrast, other review suggested that certain genes play a role in the susceptibility to PSP pathology (such as MAPT) [19].’’…’’ In a recent meta-analysis V393A was shown to be susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population [28].’’

 

Or research articles: ‘’A British family with the SNCA G51D variant shared neuropathological features of both MSA and PD [20].’’…’’ The most frequent MAPT mutation related to PSP is located at codon 279, involving 11 cases [75].’’ ..’’In another study of 127 pathologically-confirmed cases of MSA, H2 and H1E were correlated with decreased risk of MSA, whereas H1x and H1J were correlated with increased risk of MSA [45].’’ However, in a study of 108 neuropathologically- confirmed MSA cases, no link was found between GBA1 mutations and MSA [49]. Moreover, the GBA1 L444P mutation was not correlated with MSA in 54 Chinese MSA patients [50]. Additionally, no causal link was proven with 54 lysosomal storage disorder genes in 375 MSA patients [51]. Importantly, GBA mutations do not appear to  be involved in the predisposition to 167 MSA autopsy- proven series [52].’’

 

7. Some of the sections do not appear to depict the entirety of the literature and thus it appears like the authors selected particular studies and omitted others to suit their narrative. The discussion should instead be more nuanced and include studies reporting negative or divergent results as well.

OUR RESPONSE: All sections depict the  most relevant information of the literature in way to respect the length of this brief review format according to journal rules. In the discussion part I made an effort to highlight conflicting results:’’ By contrast, there is a conflicted evidence concerning the role of MAPT mutations and haplotypes in MSA development []. More studies are required to confirm the effect of other haplotypes in developing PSP or MSA.’’ Or negative results: ‘’ Although GBA mutations have been associated to others synoucleinopathies (PD, DLB) there are negative results regarding the link between GBA and MSA []. This could be explained by unknown environmental factors that may interfere with the MSA pathology. More studies should access these factors.’’

 

 

 

 

 

8. It appreciates that Author presented few tables for the selected genes in the manuscript. However, manuscript would benefit greatly if one table summarizing all of the published relevant gene findings. One approach could be a table on preclinical (mainly rodent) studies, and one on cell culture and a separate table on clinical/human studies.

OUR RESPONSE:Just because one separate with all clinical/human studies would be too large I, just find a good idea one table summarizing all of the published relevant gene mutations. On the other hand, a table on preclinical (mainly rodent) studies, or  one on cell culture it is not worth to make because there are only 3 studies.

 

 

 

9. The discussion should be more elaborative.

 OUR RESPONSE: Some parts missing refs were included through the discussion.

In the discussion, I made an effort to highlight conflicting results:’’ By contrast, there is a conflicted evidence concerning the role of MAPT mutations and haplotypes in MSA development []. More studies are required to confirm the effect of other haplotypes in developing PSP or MSA.’’ Or negative results: ‘’ Although GBA mutations have been associated to others synoucleinopathies (PD, DLB) there are negative results regarding the link between GBA and MSA []. This could be explained by unknown environmental factors that may interfere with the MSA pathology. More studies should access these factors.’’

And some more critical suggestion for future research:‘’ There are many open questions that need to be addressed by future studies. So far, few evidence has been published in patients with a PSP phenotype, [NPC1 gene, the C9orf72 gene, the parkin gene (PARK2), the transactivation response element DNA-binding protein gene (TARDBP), the progranulin gene (GRN), the TANK-binding kinase 1 gene (TBK1) and the bassoon gene (BSN)] [19]. Moreover MSA and PSP may share the same LLRK2 G2019S mutation. Given the overlapping phenotypes, there is a strong hypothesis that atypical parkinsonian syndromes may share common pathological mechanisms. May we consider neurodegeneration process as as spectrum of pathologies including MSA and PSP ? Which may be the exact role of genetics within the interplay of other factors such as environmental?’’ (lines 12-20 page16)

 

10. It would be good if author can focus and presented some data on sex/gender stratified basis.

OUR RESPONSE: Since  the majority of the included studies did not present associations between sex/gender  and  mutations, this review was not stratified on  sex/gender  basis. However, this fact was reported as a limitation in the discussion:’’ There were no associations regarding sex/gender  and mutations in the included studies.’’ (lines 25-26 page 16)

 

 

11. Ensure abbreviations are always defined at the first mention in text – this is not always the case (e.g. PSP-P, line 37 and other instances).

OUR RESPONSE: I corrected it

 

 

12. Some common errors were observed like no gap between the words and reference cited. OUR RESPONSE: common errors were corrected like no gap between the words.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Plagiarism is a major scientific misconduct and breach of trust. It cannot be simply fixed here by changing the wording of sentences. 

Author Response

I  have reduced the repetion rate on 26% internet sources, 27% publications, 6% student papers and in each paper less than 5% Please find attached here the report.

Author Response File: Author Response.pdf

Reviewer 3 Report

The response provided by Author in cover letter (e.g. page number and line number) is not matching with revised manuscript. Please refer it correctly. 

Author Response

Dear Editor,

Thank you very much for reviewing our manuscript entitled ‘’Genetics of Multiple system atrophy and Progressive supranuclear palsy: A systemised review of the literature’’

and for giving me the opportunity to publish it. I addressed all the issues raised by the reviewers.

I have amended the paper in line with the referees’ comments in yellow colour  and the revised version is attached. I have dealt with the referees’ comments as follows:

 

 

Comments and Suggestions for Authors

Reviewer  3

This manuscript covers an interesting topic, Genetics of Multiple system atrophy and Progressive supranuclear palsy: A systemised review of the literature. Overall, the manuscript has some strengths, but also various weaknesses, as outlined below. I have suggestions below as to how the manuscript could be improved.

1. The author needs to make an adequate case background for this review article, as in recent years many similar review articles have been published. The authors should cite and briefly discuss recent relevant review articles in the introduction.

OUR RESPONSE: I comment about the previous reviews : ‘’ Previous review concluded that there no susceptibility genes of MSA [18]. By contrast, other review suggested the vulnerability of certain genes to PSP pathology (such as MAPT) [19].’’ (lines 65-67 page 2)

 

 

2. Some of the sections do not appear to show a balanced description of the literature at hand, as the source of the discussed data is not put into context. Here mainly case studies are described, which are interesting but the limitations of these in terms of extrapolating to all MSA and PSP cases should be clearly stated.

 OUR RESPONSE: The aim of the present review was to discuss critically  genetic studies on MSA and PSP. By searching the bibliography, these studies were identified as case studies. Indeed, the limitations of their design nature in terms of extrapolating to all MSA and PSP cases was discussed in the discussion; ‘’ . Indeed, case studies were mainly performed, which are interesting but there are significant limitations of these in terms of extrapolating to all MSA and PSP cases [63-69, 92-100].  ‘’ (lines 340-342  page 13 )

 

3. Though author aim was not to perform the a systematic review and meta-analysis but the study design was very weak. Inclusion/exclusion criteria was not clearly defined. It will good if author present a flow diagram for study design which include the various steps of study design, including the inclusion criteria, number of studies found in initial stage, then number of study included in final stage etc.

 OUR RESPONSE: This is a narrative systemized review  as previously described [Grant, M.;Booth, A. A typology of reviews: An analysis of 14 review types and associated methodologies. Health Info Libr J 2009, 26, 91–108]. I also present the flowchart of the study selection in the Result part: ‘’  From 1.166 studies, after removing 833 duplicates, 132 reports were eligible for review according to the inclusion criteria. Finally, after full text review, 43 studies concerning PSP and MSA mutations were selected for analysis; the Figure1 presents the flowchart of the study selection.’’ (lines  74-77 page 2 )

 

4. Also, in inclusion criteria author mentioned that included human studies, animal, and cell culture studies but it is not always clear whether the studies being discussed were carried out in cell culture, mice/rodents or humans (e.g. Although tau is present in GCI [40]). Please clarify where necessary.

OUR RESPONSE: I clarify  when included human studies as:’’ The H1 haplotype was proved to be a risk for 61 MSA autopsy-proven patients [47]. By contrast, H2 and H1E were not a likelihood of 127 MSA autopsy-proven patients. H1x and H1J influence the MSA onset [48]. (lines  153-156 page4)’’…’’ No link was found among GBA1 mutations and 108 MSA neuropathologically- proven MSA patients [52]. Moreover, 54 Chinese MSA patients were negative for the GBA1 L444P mutation [53].’’ (lines 168-170 page 5)  Additionally, no causal link was proven with 54 GBA genes in 375 MSA cases [54]. Importantly, GBA mutations do not appear to be involved in the predisposition to 167 MSA autopsy- proven series [55]. (lines 171-173 page 5) 

 

Or cell- culture (in vitro studies): ‘’Despite the existence of tau in GCI [44], the implication of tau is debated on how takes place in MSA pathogenesis and development.’’ (lines 148-150  page 4) 

 

 

Or animal mice/rodents: ‘’ Moreover, functional in vitro experiments have demonstrated that the G2019S mutation exacerbate kinase function, potentially explaining the presence of tau or a-synuclein, through enhanced phosphorylation [101].’’ (lines 245-247 page 12) 

 

5. A large number of original references are missing here (e.g. PMID: 19538213), and the studies mentioned are also not exhaustive, as only 3-4 studies are mentioned here.

 OUR RESPONSE: The aim of this review was to  discuss briefly  and critically the genes that are potentially linked with MSA – SNCA, COQ2, MAPT, GBA1, LRRK2 and C9orf72 – and those associated with PSP- MAPT, LRRK2, DCTN1, NPC1, PARK2, TARDBP, GRNTBK1 and C9orf72, highlight the overlapped genetic areas of MSA and PSP, and discuss future directions. Some more important papers were added: Madzar D, Schulte C, Gasser T. Screening for LRRK2 R1441 mutations in a cohort of PSP patients from Germany. Eur J Neurol. 2009 Nov;16(11):1230-2. Katzeff, J.S, Phan, K., Purushothuman, S., Halliday, G.M., Kim, W.S. Cross-examining candidate genes implicated in multiple system atrophy. Acta Neuropathol Commun. 2019, 7(1), 117. Stefanova N, Reindl M, Poewe W, Wenning GK. In vitro models of multiple system atrophy. Mov Disord. 2005 ;20 Suppl 12:S53-6.  (see refs)

 

6. Its difficult to identify that information was taken from review article or from research articles (original references). Please clarify where necessary.

OUR RESPONSE: I clarify if the data were taken from review:’’Previous review concluded that there no susceptibility genes of MSA [18]. By contrast, other review suggested the vulnerability of certain genes to PSP pathology (such as MAPT) [19].’’ (lines 65-67 page 2)’’ In a recent meta-analysis V393A was shown to be susceptibility variant instead of causative for MSA specifically, MSA-C, in the East Asian cohorts [31].’’ (lines 120-122  page 4 )…

 

Or research articles: ‘’The SNCA G51D variant shared histopathological features of both MSA and PD [20,24].’’ (lines 101-102 page 3)…’’ The most frequent MAPT mutation related to PSP in codon 279, of eleven patients.’’  (lines  217-218 page 10).. By contrast, H2 and H1E were not a likelihood of 127 MSA autopsy-proven patients. H1x and H1J influence the MSA onset [48]. (lines  154-156 page4)’’…’’ No link was found among GBA1 mutations and 108 MSA neuropathologically- proven MSA patients [52]. Moreover, 54 Chinese MSA patients were negative for the GBA1 L444P mutation [53].’’ (lines 169-170 page 5)  Additionally, no causal link was proven with 54 GBA genes in 375 MSA cases [54]. Importantly, GBA mutations do not appear to be involved in the predisposition to 167 MSA autopsy- proven series [55]. (lines 171-173 page 5) 

 

7. Some of the sections do not appear to depict the entirety of the literature and thus it appears like the authors selected particular studies and omitted others to suit their narrative. The discussion should instead be more nuanced and include studies reporting negative or divergent results as well.

OUR RESPONSE: All sections depict the  most relevant information of the literature in way to respect the length of this brief review format according to journal rules. In the discussion part I made an effort to highlight conflicting results:’’ By contrast, there is a conflicted evidence concerning the role of MAPT mutations and haplotypes in MSA development [48]. More analysis are needed to confirm the effect of other haplotypes in developing PSP or MSA..’’(lines 304 -307 page 13)

Or negative results: ‘’ Although GBA mutations have been associated with PD and DLB, there are negative results regarding the link between GBA and MSA [54,55]. This could be explained by unknown environmental factors that may interfere with the MSA pathology. More prospective studies should access these factors.’’ (lines  308-311 page 13)

 

 

 

8. It appreciates that Author presented few tables for the selected genes in the manuscript. However, manuscript would benefit greatly if one table summarizing all of the published relevant gene findings. One approach could be a table on preclinical (mainly rodent) studies, and one on cell culture and a separate table on clinical/human studies.

OUR RESPONSE:Just because one separate with all clinical/human studies would be too large I, just find a good idea one table summarizing all of the published relevant gene mutations. On the other hand, a table on preclinical (mainly rodent) studies, or  one on cell culture it is not worth to make because there are only 3 studies.

 

 

 

9. The discussion should be more elaborative.

 OUR RESPONSE: Some parts missing refs were included through the discussion.

In the discussion, I made an effort to highlight conflicting results: ’’ By contrast, there is a conflicted evidence concerning the role of MAPT mutations and haplotypes in MSA development [48]. More analysis are needed to confirm the effect of other haplotypes in developing PSP or MSA..’’(lines 304-307 page 13)

Or negative results: ‘’ Although GBA mutations have been associated with PD and DLB, there are negative results regarding the link between GBA and MSA [54,55]. This could be explained by unknown environmental factors that may interfere with the MSA pathology. More prospective studies should access these factors.’’ (lines 308-311 page 13)

And some more critical suggestion for future research:‘’ There are many open questions that need to be addressed by future studies. A very few evidence has been published on PSP phenotype (NPC1 gene, the C9orf72 gene, the PARK2, the TARDBP, the GRN, the TBK1 and the BSN) [19]. Moreover MSA and PSP may share the same LLRK2 G2019S mutation. Given the overlapping phenotypes, there is a strong hypothesis that atypical parkinsonian syndromes may share common pathological mechanisms. May we consider neurodegeneration process as as spectrum of pathologies including MSA and PSP? Which may be the exact role of genetics within the interplay of other factors such as environmental?’’ (lines 330-337 page 13)

 

10. It would be good if author can focus and presented some data on sex/gender stratified basis.

OUR RESPONSE: Since  the majority of the included studies did not present associations between sex/gender  and  mutations, this review was not stratified on  sex/gender  basis. However, this fact was reported as a limitation in the discussion:’’ There were no associations regarding sex/gender and mutations in the included studies.’’ (lines  342-343 page 13)

 

 

11. Ensure abbreviations are always defined at the first mention in text – this is not always the case (e.g. PSP-P, line 37 and other instances).

OUR RESPONSE: I corrected it

 

 

12. Some common errors were observed like no gap between the words and reference cited. OUR RESPONSE: common errors were corrected like no gap between the words.

 

Author Response File: Author Response.docx