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Biochemical, Biomarker, and Behavioral Characterization of the GrnR493X Mouse Model of Frontotemporal Dementia

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Abstract

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.

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Acknowledgements

We thank Robert Farese, Jr., Tobias Walther, John Morley, and Thi Nguyen for helpful discussions, the Bluefield Project to Cure FTD for progranulin antibodies and Grn mouse plasma, Yuna Ayala for advice about TDP-43 analysis, Sami Barmada for qPCR primer sequences for sTDP-43 isoforms, the NeuroBehavior Laboratory at the Harvard NeuroDiscovery Center, the Quanterix Accelerator Lab, and Millipore Sigma for plasma NfL measurements using the SMC platform

Funding

This work was supported by grants from the National Institutes of Health (AG047339 and AG064069) and the Bluefield Project to Cure FTD to ADN. Research reported in this publication was also supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health.

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Authors and Affiliations

  1. Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, USA

    Denise M. Smith, Geetika Aggarwal, Michael L. Niehoff, Spencer A. Jones, Subhashis Banerjee, Susan A. Farr & Andrew D. Nguyen

  2. Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, USA

    Denise M. Smith, Geetika Aggarwal, Spencer A. Jones, Subhashis Banerjee, Susan A. Farr & Andrew D. Nguyen

  3. Institute for Translational Neuroscience, Saint Louis University, St. Louis, USA

    Denise M. Smith, Geetika Aggarwal, Spencer A. Jones, Subhashis Banerjee, Susan A. Farr & Andrew D. Nguyen

  4. Veterans Affairs Medical Center, St. Louis, USA

    Michael L. Niehoff & Susan A. Farr

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  1. Denise M. Smith
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Contributions

D. M. Smith performed experiments, analyzed data, and prepared figures. G. Aggarwal performed experiments. M. L. Niehoff performed experiments. S. A. Jones performed experiments. S. Banerjee performed experiments. S. A. Farr performed experiments, analyzed data, and prepared figures. A. D. Nguyen designed the study, analyzed data, prepared figures, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Andrew D. Nguyen.

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All methods and animal procedures were approved by the Institutional Animal Care and Use Committee at Saint Louis University or the Harvard Medical Area Standing Committee on Animals.

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Smith, D.M., Aggarwal, G., Niehoff, M.L. et al. Biochemical, Biomarker, and Behavioral Characterization of the GrnR493X Mouse Model of Frontotemporal Dementia. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04190-9

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