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Patterns of neuronal Rhes as a novel hallmark of tauopathies

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Abstract

The farnesyltransferase inhibitor, Lonafarnib, reduces tau inclusions and associated atrophy in familial tauopathy models through activation of autophagy, mediated by the inhibition of farnesylation of the Ras GTPase, Rhes. While hinting at a role of Rhes in tau aggregation, it is unclear how translatable these results are for sporadic forms of tauopathy. We examined histological slides of allocortex and neocortex from multiple postmortem cases in five different tauopathies, FTLD-TDP, and healthy controls using immunofluorescence for Rhes, several tau post-translational modifications, and phospho-TDP-43. Single nucleus RNA data suggest that Rhes is found in all cortical neuron subpopulations but not in glia. Histologic investigation showed that nearly all neurons in control brains display a pattern of diffuse cytoplasmic Rhes positivity. However, in the presence of abnormal tau, but not abnormal TDP-43, the patterns of neuronal cytoplasmic Rhes tend to present as either punctiform or entirely absent. This observation reinforces the relevance of findings that link Rhes changes and tau pathology from the in vivo and in vitro models of tauopathy. The results here support a potential clinical application of Lonafarnib to tauopathies.

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Acknowledgements

The authors thank the UCSF Memory and Aging Center patients and their families for their contributions to this work. In particular, we thank those who have donated their brains to the Neurodegenerative Disease Brain Bank. We also thank the brain bank staff, without whom this work would not be possible. Additionally, we thank the Grinberg lab staff for their technical and administrative assistance with this work. Microscopy was done at the Cancer Research Lab Molecular Imaging Center at the University of California, Berkeley. The UC Berkeley Biological Faculty Research Fund provided financial support for the appropriate equipment. We thank Feather Ives and Holly Aaron, Ph.D., for their training and assistance. This study was supported by National Institute on Aging grants K24AG053435, K08AG052648, R01AG062359, F30AG066418, and R56AG057528 as well as National Institute of Neurological Disorders and Stroke grant U54NS100717-04 with additional support from Institutional grants NIH P30 AG062422 and P01AG019724, the Rainwater Charitable Foundation, and the Larry L. Hillblom Foundation.

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Authors and Affiliations

  1. Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, 675 Nelson Rising Lane, Box 1207, San Francisco, 94158, CA, USA

    Alexander J. Ehrenberg, Caroline Lew, William W. Seeley, Salvatore Spina, Bruce Miller & Lea T. Grinberg

  2. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, USA

    Alexander J. Ehrenberg

  3. Department of Integrative Biology, University of California, Berkeley, Berkeley, USA

    Alexander J. Ehrenberg & Kaitlyn N. Letourneau

  4. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, USA

    Kun Leng & Martin Kampmann

  5. Chan Zuckerberg Biohub, San Francisco, USA

    Kun Leng & Martin Kampmann

  6. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, USA

    Kun Leng & Helmut Heinsen

  7. Medical Scientist Training Program, University of California, San Francisco, San Francisco, USA

    Kun Leng

  8. Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, USA

    Israel Hernandez & Kenneth S. Kosik

  9. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, USA

    Martin Kampmann

  10. Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, USA

    Kenneth S. Kosik

  11. Department of Pathology, University of São Paulo, São Paulo, Brazil

    Lea T. Grinberg

  12. Global Brain Health Institute, University of California, San Francisco, San Francisco, USA

    Lea T. Grinberg

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  1. Alexander J. Ehrenberg
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Correspondence to Lea T. Grinberg.

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Ehrenberg, A.J., Leng, K., Letourneau, K.N. et al. Patterns of neuronal Rhes as a novel hallmark of tauopathies. Acta Neuropathol 141, 651–666 (2021). https://doi.org/10.1007/s00401-021-02279-2

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