LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies

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  1. Note: This rebuttal was posted by the corresponding author to Review Commons. Content has not been altered except for formatting.

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    Reply to the reviewers

    Reviewer #1 (Evidence, reproducibility and clarity (Required)): Very high evidence and clarity. Excellent scientific rigor. The findings are important and reported clearly. The experiments are conducted in a rigorous way by numerous participating laboratories. Reviewer #1 (Significance (Required)): Very high significance, both from a molecular biology and clinical standpoints. This is an important manuscript that challenges the findings and conclusions of a prior high-profile paper in Science by Ma et al 2016, claiming that LAG3 is a receptor for aggregation-prone species of alpha-synuclein and that deletion of LAG3 results in reduced cell to cell …

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    Referee #3

    Evidence, reproducibility and clarity

    It was proposed that LAG3 is important in the treatment of PD and related disorders, because it functions as a receptor of pathogenic α-synuclein and the treatment with anti-LAG3 antibodies attenuated the spread of pathological α-synuclein and drastically lowered the aggregation in vitro (Mao et al, Science 2016).

    In this study, authors characterized 8 antibodies to LAG3 and investigated the presence of LAG3 in cultured cell lines, NSC-derived neural cultures, or organ homogenates for the presence of human or murine LAG3. But it was not detected in any of the neuronal samples tested. In addition, single cell (sc) RNAseq yielded only …

  3. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

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    Referee #2

    Evidence, reproducibility and clarity

    This study conclusively shows that LAG3 is not the receptor for a-synuclein that underlies the spread of synucleinopathic damage in various PD-related conditions. The paper is done extremely carefully and comprehensively. My only suggestion is to indicate the significance level in Figure 5a, as it may turn out that LAG3 is actually protective.

    Significance

    This study is of extremely high significance - we need mechanisms to deal with spectacular results in the literature that should not have been published because they are were uncompelling to begin with, but were published for various sociological/political reasons. Science won't …

  4. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

    Learn more at Review Commons


    Referee #1

    Evidence, reproducibility and clarity

    Very high evidence and clarity. Excellent scientific rigor.

    The findings are important and reported clearly. The experiments are conducted in a rigorous way by numerous participating laboratories.

    Significance

    Very high significance, both from a molecular biology and clinical standpoints. This is an important manuscript that challenges the findings and conclusions of a prior high-profile paper in Science by Ma et al 2016, claiming that LAG3 is a receptor for aggregation-prone species of alpha-synuclein and that deletion of LAG3 results in reduced cell to cell propagation of alpha-synuclein aggregates.

    The experiments in this paper …