Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation

Kelly M. Guzman, Lauren E. Brink, Guillermo Rodriguez-Bey, Richard J. Bodnar, Lisha Kuang, Bin Xing, Mara Sullivan, Hyun J. Park, Erik Koppes, Haining Zhu, Quasar Padiath, Franca Cambi

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 (FusOL cKO). The FusOL 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 FusOLcKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the FusOLcKO. Collectively, this work has uncovered a novel role of oligodendrocytic Fus in regulating myelin deposition through activation of Akt and cholesterol biosynthesis.

Original languageEnglish
Pages (from-to)2040-2056
Number of pages17
Issue number10
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
We thank Drs. T. Kozai and D. Sun, University of Pittsburgh for critical reading of the manuscript and Dr. C.B. Rogers, Nikon Instruments Inc. for assistance with application. Pilot grant from University of Kentucky (FC and HZ), I21 BX003237‐01 (FC and HZ) and Supplements (FC), start‐up funds from VA Pittsburgh (FC), R01S077284, I01BX002149 (HZ), R21 NS104384‐01A1, R33NS106087, R01NS095884 (QP), Dr. S. Watkins, Center for Biologic Imaging, University of Pittsburgh (1S10OD019973–01, 1S10RR019003–01, 1S10RR016236–01), Behavioral Testing was performed at the Rodent Behavioral Analysis Core (RBAC), University of Pittsburgh supported in part by internal funding from the Department of Neurobiology, Cholesterol quantifications were performed by the Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh (S100D023402).

Publisher Copyright:
© 2020 Wiley Periodicals, Inc.


  • Akt
  • FTLD
  • Fus
  • cholesterol
  • hyperactivity
  • myelin

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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