title: MicroRNA-27a Promotes Inefficient Lysosomal Clearance in the Hippocampi of Rats Following Chronic Brain Hypoperfusion.
abstract: Chronic brain hypoperfusion (CBH) induces the accumulation of abnormal cellular proteins, accompanied by cognitive decline, and the autophagic-lysosomal system is abnormal in dementia. Whether CBH accounts for autophagic-lysosomal neuropathology remains unknown. Here, we show that CBH significantly increased the number of autophagic vacuoles (AVs) with high LC3-II levels, but decreased SQSTM1 and cathepsin D levels in the hippocampi of rats following bilateral common carotid artery occlusion (2VO) for 2 weeks. Further studies showed that microRNA-27a (Mir27a) was upregulated at 2 weeks compared with the sham group. Additionally, LAMP-2 proteins were downregulated by Mir27a overexpression, upregulated by Mir27a inhibition, and unchanged by binding-site mutations or miR-masks, indicating that lamp-2 is the target of Mir27a. Knockdown of endogenous Mir27a prevented the reduction of LAMP-2 protein expression as well as the accumulation of AVs in the hippocampi of 2VO rats. Overexpression of Mir27a induced, while the knockdown of Mir27a reduced, the accumulation of AVs and the LC3-II level in cultured neonatal rat neurons. The results revealed that CBH in rats at 2 weeks could induce inefficient lysosomal clearance, which is regulated by the Mir27a-mediated downregulation of LAMP-2 protein expression. These findings provide an insight into a novel molecular mechanism of autophagy at the miRNA level.
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Che
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150001, China.
authors.forename: Huai-Lei
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150001, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: De-Kang
authors.initials: DK
authors.lastname: Zong
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Bao
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China.
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), No.157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, 150086, China. azhrbmu@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D001483:Base Sequence; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D015536:Down-Regulation / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000071456:Sequestosome-1 Protein; C526109:Anxa3 protein, rat; C000594049:MIRN27 microRNA, rat; C491079:Sqstm1 protein, rat
keywords: Autophagy; Chronic brain hypoperfusion; LAMP-2; Lysosome; Mir27a