Aberrant Axon Branching Via Fos-B Dysregulation in FUS-ALS Motor Neurons
79 Pages Posted: 6 Dec 2018More...
The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. In the present study, two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs were compared, and we found an abnormal increase in axon branching in the ALS-causative FUS-mutant lines. Moreover, we applied microfluidic devices that enable axon bundles to be produced for omics analysis and conducted RNA profiling of isolated axons. Thus, we identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching.
Funding Statement: This work was supported by Research and Study Project of Tokai University Educational System General Research Organization [to H.M].
Declaration of Interests: H.Ok. is a paid Scientific Advisor of SanBio Co.Ltd and K Pharma Inc. Y.O. is a scientific advisor for Kohjin Bio Co., Ltd. Other authors declare no competing financial interests.
Ethics Approval Statement: All protocols were approved by the ethics committees of Tohoku University School of Medicine (No. 2010–306) and the Keio University School of Medicine (N0. 20080016).
Keywords: amyotrophic lateral sclerosis (ALS); fused in sarcoma (FUS); axon branching; Fos-B; nerve organoid; human-induced pluripotent stem cells (hiPSCs)-derived motor neuron
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