2. Academic Validation
  3. Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment

  • JCI Insight. 2023 Jul 24;8(14):e166306. doi: 10.1172/jci.insight.166306.
Zhimeng Yao 1 2 3,  Hongmei Dong 3,  Jianlin Zhu 2 3,  Liang Du 3,  Yichen Luo 3,  Qing Liu 4,  Shixin Liu 5,  Yusheng Lin 3 6 7,  Lu Wang 3,  Shuhong Wang 3,  Wei Wei 8,  Keke Zhang 8,  Qingjun Huang 9,  Xiaojun Yu 10,  Weijiang Zhao 11 12,  Haiyun Xu 9 13,  Xiaofu Qiu 14,  Yunlong Pan 2 15,  Xingxu Huang 16,  Sai-Ching Jim Yeung 17,  Dianzheng Zhang 18,  Hao Zhang 2 19
Affiliations

Affiliations

  • 1 Department of Urology Surgery, and.
  • 2 Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China.
  • 3 Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
  • 4 Department of Pathology, The First People's Hospital of Foshan, Foshan, Guangdong, China.
  • 5 Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China.
  • 6 Graduate School, Shantou University Medical College, Shantou, Guangdong, China.
  • 7 Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
  • 8 Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
  • 9 Shantou University Mental Health Center.
  • 10 National Key Disciplines, Department of Forensic and Pathology, and.
  • 11 Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, China.
  • 12 Cell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
  • 13 The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 14 Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
  • 15 Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, Guangdong, China.
  • 16 Gene Editing Center, School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China.
  • 17 Department of Emergency Medicine and Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 18 Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA.
  • 19 Institute of Precision Cancer Medicine and Pathology, School of Medicine, and Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, Guangdong, China.
PMID: 37485875 DOI: 10.1172/jci.insight.166306
Abstract

Chemotherapy-related cognitive impairment (CRCI) or "chemo brain" is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine Phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro-/- female mice with doxorubicin (DOX) because Ptpro-/- female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that Src and EphA4 are highly phosphorylated/activated in the hippocampi of Ptpro-/- female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro-/- female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

Keywords

Aging; Behavior; Neurological disorders; Phosphoprotein phosphatases.

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