Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation. Issue 10 (18th March 2020) - Guzman, Kelly M.
Abstract: Fused in sarcoma (FUS) is a predominantly nuclear multifunctional RNA/DNA‐binding protein that regulates multiple aspects of gene expression. FUS mutations are associated with familial amyotrophic lateral sclerosis (fALS) and frontotemporal lobe degeneration (FTLD) in humans. At the molecular level, the mutated FUS protein is reduced in the nucleus but accumulates in cytoplasmic granules. Oligodendrocytes (OL) carrying clinically relevant FUS mutations contribute to non‐cell autonomous motor neuron disease progression, consistent with an extrinsic mechanism of disease mediated by OL. Knocking out FUS globally or in neurons lead to behavioral abnormalities that are similar to those present in FTLD. In this study, we sought to investigate whether an extrinsic mechanism mediated by loss of FUS function in OL contributes to the behavioral phenotype. We have generated a novel conditional knockout (cKO) in which Fus is selectively depleted in OL ( Fus OL cKO). The Fus OL cKO mice show increased novelty‐induced motor activity and enhanced exploratory behavior, which are reminiscent of some manifestations of FTLD. The phenotypes are associated with greater myelin thickness, higher number of myelinated small diameter axons without an increase in the number of mature OL. The expression of the rate‐limiting enzyme of cholesterol biosynthesis (HMGCR) is increased in white matter tracts of the Fus OL cKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the Fus OL cKO. Collectively, this work has uncovered a novel role of oligodendrocytic Fus in regulating myelin deposition through activation of Akt and cholesterol biosynthesis. Abstract : Myelin thickness and myelinated small axons are increased in Fus OL cKO mice. Activation of HMGCR expression leads to higher cholesterol in Fus OL cKO mice. Akt is activated in Fus OL cKO mice. Fus OL cKO mice exhibit enhanced exploration and motor activity