MicroRNA-27a Promotes Inefficient Lysosomal Clearance in the Hippocampi of Rats Following Chronic Brain Hypoperfusion

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...

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Bibliographic Details
Published in:Molecular neurobiology 2017-05, Vol.54 (4), p.2595-2610
Main Authors: Che, Hui, Yan, Yan, Kang, Xiao-Hui, Guo, Fei, Yan, Mei-Ling, Liu, Huai-Lei, Hou, Xu, Liu, Tong, Zong, De-Kang, Sun, Lin-Lin, Bao, Ya-Nan, Sun, Li-Hua, Yang, Bao-Feng, Ai, Jing
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - genetics
Base Sequence
Biomedical and Life Sciences
Biomedicine
Brain
Brain Ischemia - metabolism
Brain Ischemia - pathology
Cell Biology
Chronic Disease
Down-Regulation - genetics
Hippocampus - metabolism
Hippocampus - ultrastructure
Lysosomal-Associated Membrane Protein 2 - metabolism
Lysosomes - metabolism
Lysosomes - ultrastructure
Male
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
Microtubule-Associated Proteins - metabolism
Neurobiology
Neurology
Neurosciences
Phagosomes - metabolism
Phagosomes - ultrastructure
Proteins
Rats, Sprague-Dawley
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Rodents
Sequestosome-1 Protein - metabolism
Vacuoles - metabolism
Vacuoles - ultrastructure
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Summary: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.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-016-9856-8