2. Academic Validation
  3. Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage

Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage

  • Sci Adv. 2022 Sep 30;8(39):eabq2423. doi: 10.1126/sciadv.abq2423.
Dayun Feng 1,  Jinpeng Zhou 1,  Haixiao Liu 1,  Xun Wu 1,  Fei Li 1,  Junlong Zhao 2,  Yu Zhang 3,  Lei Wang 3,  Min Chao 1,  Qiang Wang 1,  Huaizhou Qin 1,  Shunnan Ge 1,  Qiang Liu 4,  Jian Zhang 5,  Yan Qu 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, International Cooperation Platform for Encephalopathy of Shaanxi Province, Xi'an 710038, China.
  • 2 Department of Medical Genetics and Development Biology, Fourth Military Medical University, Xi'an 710032, China.
  • 3 Department of Biological Sciences, Xinyang Normal University, Xinyang 464000, China.
  • 4 Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
  • 5 Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
PMID: 36179025 DOI: 10.1126/sciadv.abq2423
Abstract

Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased Matrix Metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of SMAD2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein Phosphatase PPM1A and restricted the dephosphorylation of SMAD2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce SMAD2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.

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