Knockdown of RUVBL2 improves hnRNPA2/B1-stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats

Zixuan Wang; Chenyi Yang; Xinyi Wang; Huihui Liao; Xing Liu; Huan Liu; Miao Zhang; Lin Zhang; Haiyun Wang

doi:10.1111/acel.14418

Knockdown of RUVBL2 improves hnRNPA2/B1-stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats

Aging Cell. 2024 Nov 28:e14418. doi: 10.1111/acel.14418. Online ahead of print.

Authors

Zixuan Wang^{1

2

3

4}, Chenyi Yang⁵, Xinyi Wang^{2

3

4

5

6}, Huihui Liao^{1

2

3

4}, Xing Liu^{1

2

3

4}, Huan Liu^{1

2

3

4}, Miao Zhang^{1

2

3

4}, Lin Zhang^{1

2

3

4}, Haiyun Wang^{1

2

3

4

5

6}

Affiliations

¹ The Third Central Clinical College of Tianjin Medical University, Tianjin, China.
² Department of Anesthesiology, The Third Central Hospital of Tianjin, Tianjin, China.
³ Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China.
⁴ Artificial Cell Engineering Technology Research Center, Tianjin, China.
⁵ Nankai University, Tianjin, China.
⁶ Nankai University Affinity The Third Central Hospital, Tianjin, China.

PMID: 39610020
DOI: 10.1111/acel.14418

Abstract

Perioperative neurocognitive disorders (PND) is common in aged mild cognitive impairment (MCI) patients and can accelerate the progression to dementia. This process involves heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1)-mediated aggregates of stress granules (SGs), while RUVBL2 influences the dynamics of these SGs. Our research explored a new target for modulating hnRNAPA2/B1-SGs dynamics to accelerate their disassembly and potentially delay MCI progression due to PND. We assessed the effect of hippocampal RUVBL2 knockdown on hnRNPA2/B1-SGs in aged MCI rats through behavioral studies, biochemical experiments and MRI. We also examined hnRNPA2/B1-SGs dynamics using immunofluorescence staining and fluorescence recovery after photobleaching (FRAP) in rat primary hippocampal neurons. Our results revealed that hnRNPA2/B1 in the hippocampus of aged MCI rats translocates to the cytoplasm to form SGs following anesthesia. RUVBL2 knockdown promotes the disappearance of hnRNPA2/B1-SGs, allowing hnRNPA2/B1 to return to the nucleus and enhancing functional activity in the brain regions of aged MCI rats. In primary hippocampal neurons, RUVBL2 deletion facilitated hnRNPA2/B1-SGs transition from hydrogel to liquid, promoting disassembly. We compared three commonly used general anesthetics-3% sevoflurane, 40 mg·kg^-1·h^-1 propofol, and 9% desflurane. Sevoflurane upregulated RUVBL2, which decreased the intraneuronal pH and disrupted energy metabolism. These changes resulted in greater stabilization of hnRNPA2/B1- SGs. In conclusion, our findings indicated that the knockdown of RUVBL2 expression contributes to the transition of hnRNPA2/B1-SGs from the hydrogel phase to the liquid phase. Targeted interference with RUVBL2 may represent a novel approach to delay the progression to dementia due to PND in aged MCI patients.

Keywords: RUVBL2; aged mild cognitive impairment; dynamics; hnRNPA2/B1; perioperative neurocognitive disorders; stress granules.

Abstract

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