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Nuclear Inhibitor of Protein Phosphatase 1 (NIPP1) Regulates CNS Tau Phosphorylation and Myelination During Development

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Abstract

Nuclear inhibitor of protein phosphatase 1 (NIPP1) is a known regulator of gene expression and plays roles in many physiological or pathological processes such as stem cell proliferation and skin inflammation. While NIPP1 has many regulatory roles in proliferating cells, its function in the central nervous system (CNS) has not been directly investigated. In the present study, we examined NIPP1 CNS function using a conditional knockout (cKO) mouse model in which the Nipp1 gene is excised from neural precursor cells. These mice exhibited severe developmental impairments that led to premature lethality. To delineate the neurological changes occurring in these animals, we first assessed microtubule-associated protein tau, a known target of NIPP1 activity. We found that phosphorylation of tau is significantly enhanced in NIPP1 cKO mice. Consistent with this, we found altered AKT and PP1 activity in NIPP1 cKO mice, suggesting that increased tau phosphorylation likely results from a shift in kinase/phosphatase activity. Secondly, we observed tremors in the NIPP1 cKO mice which prompted us to explore the integrity of the myelin sheath, an integral structure for CNS function. We demonstrated that in NIPP1 cKO mice, there is a significant decrease in MBP protein expression in the cortex, along with deficits in both the conduction of compound action potentials (CAP) and the percentage of myelinated axons in the optic nerve. Our study suggests that NIPP1 in neural precursor cells regulates phosphorylation of tau and CNS myelination and may represent a novel therapeutic target for neurodegenerative diseases.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the technical help of Karen Bentley, director of Electron Microscopy Core of URMC, and Drs. Mathieu Bollen and Aleyde Van Eynde (KU Leuven, Belgium) for providing the floxed NIPP1 mice in our study.

Funding

This work is supported by the National Institutes of Health (NIH) (R01 MH109719) and the National Science Foundation (NSF) (IOS-1457336) to HX and the NIH (F30 MH122046) to KF.

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Authors and Affiliations

  1. Neuroscience Graduate Program, Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Cody McKee, Peter Shrager, Abigail Mayer, Karl Foley, Margaret Youngman & Houhui Xia

  2. Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Arindam Gosh Mazumder, Archan Ganguly, Nancy Ward, Hailong Hou & Houhui Xia

Authors
  1. Cody McKee
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  2. Peter Shrager
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  3. Arindam Gosh Mazumder
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  9. Hailong Hou
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  10. Houhui Xia
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Contributions

Houhui Xia contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Cody McKee, Peter Shrager, Arindam Gosh Mazumder, Archan Ganguly, Abigail Mayer, Karl Foley, Nancy Ward, Margaret Youngman, and Hailong Hou. The first draft of the manuscript was written by Houhui Xia and Cody McKee, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hailong Hou or Houhui Xia.

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Ethics Approval

All mouse experiments were performed in accordance with protocols approved by the University Committee on Animal Resources of the University of Rochester Medical Center (URMC). Our experiments comply with the ARRIVE guidelines and were carried out in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals.

Research Involving Human Participants and/or Animals

Our research involved use of animals, but not of human subjects.

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Not applicable. There are no human subjects involved in our study.

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McKee, C., Shrager, P., Mazumder, A.G. et al. Nuclear Inhibitor of Protein Phosphatase 1 (NIPP1) Regulates CNS Tau Phosphorylation and Myelination During Development. Mol Neurobiol 59, 7486–7494 (2022). https://doi.org/10.1007/s12035-022-03040-w

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