Biology subjects

Shrager, P.

Publications and source records attributed to Shrager, P..

4 recordsLinked to original sources

bioRxiv2024

Neuronal protein phosphatase 1β regulates glutamate release, cortical myelination, node of Ranvier formation, and action potential propagation in the optic nerve

Precise regulation of protein phosphorylation is critical for many cellular processes, and dysfunction in this process has been linked to various neurological disorders and diseases. Protein phosphatase 1 (PP1) is a ubiquitously expressed serine/threonine phosphatase with three major isoforms, (, {beta}, {gamma}) and hundreds of known substrates. Previously, we reported that PP1 and PP1{gamma} are essential for the known role of PP1 in synaptic physiology and learning/memory, while PP1{beta} displayed a surprising opposing function. De novo mutations in PP1{beta} cause neurodevelopmental disorders in humans, but the mechanisms involved are currently unknown. A Cre-Lox system was used to delete PP1{beta} specifically in neurons in order to study its effects on developing mice. These animals fail to survive to 3 postnatal weeks, and exhibit deficits in cortical myelination and glutamate release. There was defective compound action potential (CAP) propagation in the optic nerve of the null mice, which was traced to a deficit in the formation of nodes of Ranvier. Finally, it was found that phosphorylation of the PP1{beta}-specific substrate, myosin light chain 2 (MLC2), is significantly enhanced in PP1{beta} null optic nerves. Several novel important in vivo roles of PP1{beta} in neurons were discovered, and these data will aid future investigations in delineating the mechanisms by which de novo mutations in PP1{beta} lead to intellectual and developmental delays in patients.

neuroscience↗

bioRxiv2024

Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration.

Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate that Sarm1 is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve, Sarm1 is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. In Sarm1-/- mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment of Sarm1-/- distal nerve tissue was demonstrated by grafting of Sarm1-/- nerve into WT recipients. SC lineage tracing in injured WT and Sarm1-/- mice revealed morphological differences. In the Sarm1-/- distal nerve, the appearance of p75NTR+, c-Jun+ SCs is significantly delayed. Ex vivo, p75NTR and c-Jun upregulation in Sarm1-/- nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show that Sarm1 is not necessary for the activation of neuron intrinsic growth programs but in the distal nerve is required for the orchestration of cellular programs that underlie rapid axon extension.

neuroscience↗

bioRxiv2022

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

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 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 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 in neural precursors regulates phosphorylation of tau and CNS myelination and may represent a novel therapeutic target for neurodegenerative diseases.

neuroscience↗

bioRxiv2017

LRP1 Regulates Peroxisome Biogenesis and Cholesterol Homeostasis in Oligodendrocytes and is Required in CNS Myelin Development and Repair

The low-density lipoprotein related-receptor-1 (LRP1) is a large endocytic and signaling receptor. We show that Lrp1 is required for proper CNS myelinogensis in vivo. Either global inducible or oligodendrocyte (OL)-lineage specific ablation of Lrp1 impairs myelin development and adult white matter repair. In primary oligodendrocyte progenitor cells (OPCs), Lrp1 deficiency reduces cholesterol levels and attenuates differentiation into mature OLs. Despite a strong increase in the sterol-regulatory element-binding protein-2, Lrp1-/- OPCs are not able to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies identified a decrease in peroxisomal biogenesis factor-2 and a reduction in peroxisomes localized to OL processes. Treatment of Lrp1-/- OPCs with cholesterol or pharmacological activation of peroxisome proliferator-activated receptor-{gamma} with pioglitazone is not sufficient to promote differentiation; however when combined, cholesterol and pioglitazone treatment enhance OL production. Collectively, our studies identify a novel link between LRP1, peroxisomes, and OPC differentiation during white matter development and repair.

neuroscience↗