Nuclear inhibitor of protein phosphatase 1 (NIPP1) regulates CNS tau phosphorylation and myelination during development

Abstract: Nuclear inhibitor of protein phosphatase 1 (NIPP1) is a known regulator of gene expression and has been shown to play roles in many physiological or pathological processes such as stem cell proliferation and development, and skin inflammation. While NIPP1 has many regulatory roles in proliferating cells, its function in the 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 demonstrate severe developmental impairments that lead to premature lethality within the first few postnatal weeks. To delineate some of the neurological changes occurring in these animals, we first assessed microtubule associated protein tau, a known target of NIPP1 activity. Furthermore, observed tremors prompted exploration of myelin integrity, an integral structure for CNS function, whose disruption is associated with various neurological disorders and neurodegenerative diseases. First, immunoblotting demonstrated increased phospho-tau and altered AKT and PP1 activity in NIPP1 cKO mice, suggesting increased tau phosphorylation likely results from a shift in kinase/phosphatase activity. Second, immunoblots, electron microscopy, and electrophysiology demonstrated a myelin deficit within the brain and optic nerve. Our study suggests that NIPP1 activity in neural precursors regulates phosphorylation of tau and CNS myelination and may represent a novel therapeutic target for neurodegenerative diseases.