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

doi:10.1016/j.celrep.2019.06.002

SFRS11 Loss Leads to Aging-Associated Cognitive Decline by Modulating LRP8 and ApoE

Cell Rep. 2019 Jul 2;28(1):78-90.e6. doi: 10.1016/j.celrep.2019.06.002.

Authors

Obayed Raihan¹, Afrina Brishti¹, Qin Li¹, Qilun Zhang¹, Dingfeng Li¹, Xiaohui Li¹, Qingyang Zhang¹, Zhongwen Xie², Jiali Li³, Juan Zhang⁴, Qiang Liu⁵

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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. Electronic address: zj2014@ustc.edu.cn.
⁵ 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. Electronic address: liuq2012@ustc.edu.cn.

PMID: 31269452
DOI: 10.1016/j.celrep.2019.06.002

Abstract

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.

Keywords: ApoE; LRP8; PFC; SFRS11; aging; cognitive decline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Aging
Animals
Apolipoproteins E / genetics
Apolipoproteins E / metabolism*
Cell Line
Cognitive Dysfunction / genetics
Cognitive Dysfunction / metabolism*
Exons
Gene Knockdown Techniques
Gene Ontology
Humans
LDL-Receptor Related Proteins / genetics
LDL-Receptor Related Proteins / metabolism*
MAP Kinase Kinase 4 / antagonists & inhibitors
MAP Kinase Kinase 4 / metabolism
MAP Kinase Signaling System / genetics
Maze Learning / physiology
Memory / physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / metabolism
Prefrontal Cortex / metabolism*
Serine-Arginine Splicing Factors / genetics
Serine-Arginine Splicing Factors / metabolism*
Signal Transduction / genetics

Substances

3' Untranslated Regions
Apoe protein, mouse
Apolipoproteins E
LDL-Receptor Related Proteins
Sfrs11 protein, mouse
low density lipoprotein receptor-related protein 8
Serine-Arginine Splicing Factors
MAP Kinase Kinase 4