TY - JOUR
T1 - Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis
AU - Jeong, Ye Eun
AU - Rajbhandari, Labchan
AU - Kim, Byung Woo
AU - Venkatesan, Arun
AU - Hoke, Ahmet
N1 - Funding Information:
The authors are thankful to Lee J. Martin, Peter Calabresi, and Donald J. Zack for discussion and valuable inputs for our study. We thank Michele Pucak at Multiphoton Imaging Core (Johns Hopkins University) and Carol Cooke at Neuromuscular Pathology Laboratory (Johns Hopkins University) for their technical advice and assistance on imaging and data analysis. We also thank Chen Wang, Yiming Zhang, and Zhigang He at the Boston Children's Hospital Viral Core for technical assistance in virus work. This work was supported by grants from Race to Erase MS Foundation and Dr. Miriam and Sheldon G. Adelson Medical Foundation and a generous donation from the Merkin Family Foundation.
Funding Information:
The authors are thankful to Lee J. Martin, Peter Calabresi, and Donald J. Zack for discussion and valuable inputs for our study. We thank Michele Pucak at Multiphoton Imaging Core (Johns Hopkins University) and Carol Cooke at Neuromuscular Pathology Laboratory (Johns Hopkins University) for their technical advice and assistance on imaging and data analysis. We also thank Chen Wang, Yiming Zhang, and Zhigang He at the Boston Children's Hospital Viral Core for technical assistance in virus work. This work was supported by grants from Race to Erase MS Foundation and Dr. Miriam and Sheldon G. Adelson Medical Foundation and a generous donation from the Merkin Family Foundation.
Publisher Copyright:
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2023/2
Y1 - 2023/2
N2 - Objective: Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long-term neurological disabilities that are not amenable to current immunomodulatory therapies. Methods and Results: Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)-induced mice. By employing an in vitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury-response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration. Interpretation: Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.
AB - Objective: Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long-term neurological disabilities that are not amenable to current immunomodulatory therapies. Methods and Results: Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)-induced mice. By employing an in vitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury-response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration. Interpretation: Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.
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U2 - 10.1002/acn3.51717
DO - 10.1002/acn3.51717
M3 - Article
C2 - 36574260
AN - SCOPUS:85145181968
SN - 2328-9503
VL - 10
SP - 246
EP - 265
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 2
ER -