Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization

Chao Yu; Jing Zhao; Feng Cheng; Jiangjie Chen; Jinyang Chen; Haibin Xu; Kesi Shi; Kaishun Xia; Siwen Ding; Kanbin Wang; Ronghao Wang; Yazhou Chen; Yi Li; Hao Li; Qixin Chen; Xiaohua Yu; Fangwei Shao; Chengzhen Liang; Fangcai Li

doi:10.34133/research.0336

Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization

Research (Wash D C). 2024 Mar 23:7:0336. doi: 10.34133/research.0336. eCollection 2024.

Authors

Chao Yu^{1

2

3

4}, Jing Zhao⁵, Feng Cheng^{1

2

3

4}, Jiangjie Chen^{1

2

3

4}, Jinyang Chen^{1

2

3

4}, Haibin Xu^{1

2

3

4}, Kesi Shi^{1

2

3

4}, Kaishun Xia^{1

2

3

4}, Siwen Ding⁶, Kanbin Wang^{1

2

3

4}, Ronghao Wang^{1

2

3

4}, Yazhou Chen^{1

2

3

4}, Yi Li^{1

2

3

4}, Hao Li^{1

2

3

4}, Qixin Chen^{1

2

3

4}, Xiaohua Yu^{1

2

3

4}, Fangwei Shao^{7

8}, Chengzhen Liang^{1

2

3

4}, Fangcai Li^{1

2

3

4}

Affiliations

¹ Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, PR China.
² Orthopedics Research Institute of Zhejiang University, Zhejiang University, Hangzhou 310009, Zhejiang, PR China.
³ Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310009, Zhejiang, PR China.
⁴ Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310009, Zhejiang, PR China.
⁵ Department of Chemistry, Zhejiang University, Hangzhou 310009, Zhejiang, PR China.
⁶ Westlake Street Community Health Service Center, Hangzhou 310009, Zhejiang, PR China.
⁷ Zhejiang University-University of Illinois at Urbana-Champaign Institute, Zhejiang University, Haining 314400, Zhejiang, PR China.
⁸ Biomedical and Health Translational Research Centre, Zhejiang University, Haining 314400, Zhejiang, PR China.

Abstract

Circular RNAs (circRNAs) play a critical regulatory role in degenerative diseases; however, their functions and therapeutic applications in intervertebral disc degeneration (IVDD) have not been explored. Here, we identified that a novel circATXN1 highly accumulates in aging nucleus pulposus cells (NPCs) accountable for IVDD. CircATXN1 accelerates cellular senescence, disrupts extracellular matrix organization, and inhibits mitochondrial respiration. Mechanistically, circATXN1, regulated by heterogeneous nuclear ribonucleoprotein A2B1-mediated splicing circularization, promotes progerin translocation from the cell nucleus to the cytoplasm and inhibits the expression of insulin-like growth factor 1 receptor (IGF-1R). To demonstrate the therapeutic potential of circATXN1, siRNA targeting the backsplice junction of circATNX1 was screened and delivered by tetrahedral framework nucleic acids (tFNAs) due to their unique compositional and tetrahedral structural features. Our siRNA delivery system demonstrates superior abilities to transfect aging cells, clear intracellular ROS, and enhanced biological safety. Using siRNA-tFNAs to silence circATXN1, aging NPCs exhibit reduced mislocalization of progerin in the cytoplasm and up-regulation of IGF-1R, thereby demonstrating a rejuvenated cellular phenotype and improved mitochondrial function. In vivo, administering an aging cell-adapted siRNA nucleic acid framework delivery system to progerin pathologically expressed premature aging mice (zmpste24^-/-) can ameliorate the cellular matrix in the nucleus pulposus tissue, effectively delaying IVDD. This study not only identified circATXN1 functioning as a cell senescence promoter in IVDD for the first time, but also successfully demonstrated its therapeutic potential via a tFNA-based siRNA delivery strategy.