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  1. Evaluation Summary:

    Patients with Gaucher disease can have significant and crippling neurological manifestations. The study uses novel mouse models of neurodegeneration associated with glucocerebrosidase 1 (GBA1) deficiency. It provides a detailed analysis of the alterations caused by targeted deletion of GBA1, including cellular, genetic and metabolic alterations in neurons, microglia, and infiltrating immune cells. The work defines novel mechanisms driving neuroinflammation in neuronopathic Gaucher disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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  3. Reviewer #1 (Public Review):

    This study by Boddupalli et al. demonstrated the roles of Gba in individual cells such as microglia, blood-derived macrophages, and astrocytes in the neuronopathic Gaucher Disease (nGD), a neurodegenerative disorder caused by biallelic mutations in Gba. The authors applied single-cell resolution of mouse nGD brains to reveal the induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons. They also found that targeted rescue of Gba in microglia or neurons, respectively in Gba deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), reduced the level of serum neurofilament light chain (Nf-L), and improved survival. Together with other related findings in this paper, this study delineated individual cellular effects of Gba deficiency in nGD brains. The experiments were well designed and conducted, the results were reasonably interpreted, and the manuscript was clearly written with logical inputs.

    One weak point is that it remained unclear or not addressed about the brain region or tissue-specific involvement in the observed phenotypes in this study.

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  5. Reviewer #2 (Public Review):

    In this manuscript, Boddupalli et al. did a detailed analysis of the alterations caused by targeted deletion of GBA1, using new mouse models of GBA1-associated neurodegeneration. This included a study of the cellular, genetic and metabolic alterations in neurons, microglia, and infiltrating immune cells, caused by GBA1 deficiency. The work clarified some of the mechanisms driving neuroinflammation in neuronopathic Gaucher disease (nGD). The methods used, including single-cell RNA sequencing are state-of-the-art, and the data are of high quality. The results fully support the main conclusions of the paper, and the data sets will be useful to other investigators in the field.

    This paper shows the deregulation of important neuroinflammatory networks at a single cell resolution level. Targeted rescue of Gba in microglia and in neurons of nGD mice reversed the buildup of glucosphingolipids with reversal of neuroinflammation. The authors also identified early biomarkers to follow disease progression and response to treatment, which were validated using sera from patients with type 3 and type 1 GD. The new markers identified included Nf-L and ApoE. Nf-L was elevated 2,000-fold in nGD mice, and there were also substantial elevations in adult GD1 patients compared to control adults. The authors also found significant differences in these disease markers between young and older GD1 patients. Nf-L and ApoE levels in the mutant mice and nGD patients were significantly reduced by brain-penetrant GluCer synthase inhibitors, further implicating elevated glucosphingolipids in the pathogenesis of GBA1-associated neurodegeneration, and validating substrate reduction as a useful therapy.

    These results of this ground-breaking study are critically important for therapeutic development, as there is an unmet need to identify GD patients and GD carriers at risk for PD/LBD. In sum, the results presented are of great clinical significance.

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