Dear Dr Deane,

Thank you for submitting your manuscript entitled "Plasma Membrane Remodelling in GM2 Gangliosidoses Drives Synaptic Dysfunction" for consideration as a Research Article by PLOS Biology. We understand that your study has been revised in response to reviews from Review Commons. We have now had a chance to discuss your study, the reviews, and your response to reviewers with an Academic Editor with relevant expertise, and I am writing to let you know that we would like to send your submission back to the original reviewers for their input on the revision.

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Feel free to email us at plosbiology@plos.org if you have any queries relating to your submission.

Kind regards,

Luke

Lucas Smith, Ph.D.

Senior Editor

PLOS Biology

lsmith@plos.org

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Submitted filename: 151284_1_rebuttal_3325368_st233r.pdf

Dear Dr Deane,

Thank you for your patience while we considered your revised manuscript "Plasma Membrane Remodelling in GM2 Gangliosidoses Drives Synaptic Dysfunction" for publication as a Research Article at PLOS Biology. This revised version of your manuscript has been evaluated by the PLOS Biology editors and two of the original reviewers from Review Commons. Please note that we asked reviewer 1 to also act as the Academic Editor for your paper.

As you will see, below, both reviewers have suggested that we accept your study. However, before we can accept your paper, we would like to invite you to address a number of editorial, data, and other policy-related requests in a last, short revision. These requests are detailed below.

**IMPORTANT: Please address the following editorial requests:

1) FINANCIAL DISCLOSURES: Please update your financial disclosures statement in our electronic system to include the grant numbers for all grants, the URL of each funder website, and a statement indicating if the sponsors or funders played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

2) DATA: I see that you indicate that you will provide your mass spec data, glycan data, and EM images via various repositories and in the supplement. Please do go ahead and do that at this stage, as these data will need to be made available before we can publish your study. Please ensure that data deposited in a repository has a DOI, and provide that to us in your data availability statement.

3) DATA: In addition to the data listed above, to be compliant with our data policy, we will need you to provide the underlying data for all the other figures in your paper. (See the full PLOS Data Policy, which requires that all data be made available without restriction, here: http://journals.plos.org/plosbiology/s/data-availability)

Note that for most of the figures, we would not require all raw data. Rather, we ask that all individual quantitative observations that underlie the data summarized in the figures and results of your paper be made available in one of the following forms:

a. Supplementary files (e.g., excel). Please ensure that all data files are uploaded as 'Supporting Information' and are invariably referred to (in the manuscript, figure legends, and the Description field when uploading your files) using the following format verbatim: S1 Data, S2 Data, etc. Multiple panels of a single or even several figures can be included as multiple sheets in one excel file that is saved using exactly the following convention: S1_Data.xlsx (using an underscore).

b. Deposition in a publicly available repository. Please also provide the accession code or a reviewer link so that we may view your data before publication.

>>Regardless of the method selected, please ensure that you provide the individual numerical values that underlie the summary data displayed in the following figure panels as they are essential for readers to assess your analysis and to reproduce it:

Fig 1C-F; Fig 2A-B; Fig 4A-E; Fig 5A-D;

Fig S1; Fig S4; Fig S5

NOTE: the numerical data provided should include all replicates AND the way in which the plotted mean and errors were derived (it should not present only the mean/average values).

>>Please also ensure that figure legends in your manuscript include information on where the underlying data can be found, and ensure your supplemental data file/s has a legend.

>>Please ensure that your Data Statement in the submission system accurately describes where your data can be found.

4) CODE: Per journal policy, if you have generated any custom code during the course of this investigation, please make it available without restrictions. Please ensure that the code is sufficiently well documented and reusable, and that your Data Statement in the Editorial Manager submission system accurately describes where your code can be found.

Please note that we cannot accept sole deposition of code in GitHub, as this could be changed after publication. However, you can archive this version of your publicly available GitHub code to Zenodo. Once you do this, it will generate a DOI number, which you will need to provide in the Data Accessibility Statement (you are welcome to also provide the GitHub access information). See the process for doing this here: https://docs.github.com/en/repositories/archiving-a-github-repository/referencing-and-citing-content

5) METHODS: I noticed that some of the methods are included in the supplemental material. Please move these to the main text.

As you address these items, please take this last chance to review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the cover letter that accompanies your revised manuscript.

In addition to these revisions, you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests shortly.

We expect to receive your revised manuscript within two weeks.

To submit your revision, please go to https://www.editorialmanager.com/pbiology/ and log in as an Author. Click the link labelled 'Submissions Needing Revision' to find your submission record. Your revised submission must include the following:

- a cover letter that should detail your responses to any editorial requests, if applicable, and whether changes have been made to the reference list

- a Response to Reviewers file that provides a detailed response to the reviewers' comments (if applicable, if not applicable please do not delete your existing 'Response to Reviewers' file.)

- a track-changes file indicating any changes that you have made to the manuscript.

NOTE: If Supporting Information files are included with your article, note that these are not copyedited and will be published as they are submitted. Please ensure that these files are legible and of high quality (at least 300 dpi) in an easily accessible file format. For this reason, please be aware that any references listed in an SI file will not be indexed. For more information, see our Supporting Information guidelines:

https://journals.plos.org/plosbiology/s/supporting-information

*Published Peer Review History*

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*Press*

Should you, your institution's press office or the journal office choose to press release your paper, please ensure you have opted out of Early Article Posting on the submission form. We ask that you notify us as soon as possible if you or your institution is planning to press release the article.

*Protocols deposition*

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please do not hesitate to contact me should you have any questions.

Sincerely,

Luke

Lucas Smith, Ph.D.

Senior Editor

lsmith@plos.org

PLOS Biology

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Reviewer remarks:

Reviewer #1 (who also agreed to serve as the Academic Editor for this study): The authors have sufficiently addressed my comments. Although some points remain to be clarified, I believe the evidence they present should be shared with the community.

Reviewer #2, Ulf Dettmer (note, reviewer 2 has signed this review): The authors did a good job addressing questions from all reviewers.

My key comment #7 has only been partially answered, but future studies will hopefully clarify things further.

Best of luck with your research.

Ulf

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Submitted filename: 151284_1_rebuttal_3325368_st233r_auresp_1.pdf

Dear Janet,

Thank you for the submission of your revised Research Article "Plasma Membrane Remodelling in GM2 Gangliosidoses Drives Synaptic Dysfunction" for publication in PLOS Biology and thank you for addressing our last editorial requests in this revision. On behalf of my colleagues and the Academic Editor, Giovanni D'Angelo, I am pleased to say that we can in principle accept your manuscript for publication, provided you address any remaining formatting and reporting issues. These will be detailed in an email you should receive within 2-3 business days from our colleagues in the journal operations team; no action is required from you until then. Please note that we will not be able to formally accept your manuscript and schedule it for publication until you have completed any requested changes.

Please take a minute to log into Editorial Manager at http://www.editorialmanager.com/pbiology/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with biologypress@plos.org. If you have previously opted in to the early version process, we ask that you notify us immediately of any press plans so that we may opt out on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for choosing PLOS Biology for publication and supporting Open Access publishing. We look forward to publishing your study. 

Sincerely, 

Luke

Lucas Smith, Ph.D.

Senior Editor

PLOS Biology

lsmith@plos.org

Attachments

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Submitted filename: 151284_1_rebuttal_3325368_st233r_auresp_2.pdf