SFRS11 Loss Leads to Aging-Associated Cognitive Decline by Modulating LRP8 and ApoE
Obayed Raihan,
Afrina Brishti,
Qin Li,
Qilun Zhang,
Dingfeng Li,
Xiaohui Li,
Qingyang Zhang,
Zhongwen Xie,
Jiali Li,
Juan Zhang,
Qiang Liu
Affiliations
Obayed Raihan
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Afrina Brishti
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Qin Li
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Qilun Zhang
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Dingfeng Li
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Xiaohui Li
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Qingyang Zhang
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China
Zhongwen Xie
State Key Laboratory of Tea Plant Biology and Utilization, College of Tea and Food Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui Province, China
Jiali Li
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
Juan Zhang
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China; Corresponding author
Qiang Liu
The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei 230026, China; National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei 230029, China; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China; Corresponding author
Summary: RNA binding proteins, the key regulators in gene expression at the posttranscriptional level, remain largely uncharacterized with respect to aging and relevant cognitive deterioration. Here, we report that the levels of SFRS11 are substantially decreased in the prefrontal cortex (PFC) of aged brains. Notably, mice with SFRS11 deficiency in the PFC show impaired learning and memory. We demonstrate that SFRS11 directly binds to the 3′ UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. Importantly, restoration of LRP8 and apoE reduces JNK signaling that is significantly enhanced in SFRS11-deficient cells. In addition, LRP8 and apoE rescue aging-like phenotypes induced by SFRS11 loss. Our findings demonstrate that age-dependent loss of SFRS11 in the PFC reduces levels of apoE and LRP8, leading to activation of the JNK pathway, ultimately influencing cognitive deficits. : Raihan et al. describe a role of SFRS11 in prefrontal cortex, which is required for higher cognitive functions. They show that SFRS11 regulates LRP8/apoE/JNK signaling, a pathway involved in cognition that declines in aging. Keywords: SFRS11, PFC, cognitive decline, LRP8, ApoE, aging
