1.SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation.
Yichen LI ; Shuaiyao LU ; Jinge GU ; Wencheng XIA ; Shengnan ZHANG ; Shenqing ZHANG ; Yan WANG ; Chong ZHANG ; Yunpeng SUN ; Jian LEI ; Cong LIU ; Zhaoming SU ; Juntao YANG ; Xiaozhong PENG ; Dan LI
Protein & Cell 2022;13(8):602-614
The nucleocapsid (N) protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation, which enables its incorporation into stress granules (SGs) of host cells. However, whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow, neither do we know its consequence. Here, we used SARS-CoV-2 to infect mammalian cells and observed the incorporation of N protein into SGs, which resulted in markedly impaired self-disassembly but stimulated cell cellular clearance of SGs. NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific transient interactions, which not only expedites the phase transition of these proteins to aberrant amyloid aggregation in vitro, but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells. In addition, we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells. Our work indicates that SARS-CoV-2 infection can impair the disassembly of host SGs and promote the aggregation of SG-related amyloid proteins, which may lead to an increased risk of neurodegeneration.
Amyloidogenic Proteins/metabolism*
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Amyotrophic Lateral Sclerosis/genetics*
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Animals
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COVID-19
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Cytoplasmic Granules/metabolism*
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Mammals
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SARS-CoV-2
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Stress Granules
2.Influence of H102 on the expression of amyloid protein and amyloid precursor protein in the hippocampus of APP695 transgenic mice.
Yan-Ling XU ; Juan ZHAO ; Rui-Yu MA ; Shu-Mei XU
Chinese Journal of Applied Physiology 2010;26(3):302-306
OBJECTIVETo observe the influence of H102 on the expression of amyloid protein and amyloid precursor protein in the hippocampus of APP695 transgenic mice.
METHODSThe 9-month-old APP695 transgenic mice were randomly divided into the model group and the H102 group; C57BL/6J mice were adopted as normal control group. The H102 group were injected with H102 in a dose of 3 microl/per mouse in lateral ventricle, once a day, for ten days; while the model group and the control group were injected with saline. The hippocampus and temporal cortex of the brain sections from transgenic mice and wild type female mice were subjected to immunohistochemistry and Congo red histological staining, and observed the difference of the protein expression under microscope. The expression of the APP protein was detected by Western blot.
RESULTSAbeta and APP immunohistochemistry showed density of positive cell in the CA1 region of hippocampus of control group were less than model group. H102 peptide reduced the area, and density of positive cells. Congo red staining showed there were lots of amyloid plagues in the brains of model mice but not in the brains of normal control. And the Western blot showed the content of the APP protein of the model group was much higher than the H102 group. H102 significantly decreased the amyloid plagues.
CONCLUSIONThe expression of APP, Abeta are increased in APP695 transgenic mice, and H102 can decrease the level of APP, Abeta in transgenic mice.
Amyloid beta-Protein Precursor ; metabolism ; Amyloidogenic Proteins ; metabolism ; Animals ; Brain ; metabolism ; Female ; Gene Expression ; Hippocampus ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic
3.Impact of sub-chronic aluminium-maltolate exposure on catabolism of amyloid precursor protein in rats.
Rui Feng LIANG ; Wei Qing LI ; Hong WANG ; Jun Xia WANG ; Qiao NIU
Biomedical and Environmental Sciences 2013;26(6):445-452
OBJECTIVETo investigate the impact of sub-chronic Aluminium-maltolate [Al(mal)3] exposure on the catabolism of amyloid precursor protein (APP) in rats.
METHODSForty adult male Sprague-Dawley (SD) rats were randomly divided into five groups: the control group, the maltolate group (7.56 mg/kg BW), and the Al(mal)3 groups (0.27, 0.54, and 1.08 mg/kg BW, respectively). Control rats were administered with 0.9% normal saline through intraperitoneal (i.p.) injection. Maltolate and Al(mal)3 were administered to the rats also through i.p. injections. Administration was conducted daily for two months. Rat neural behavior was examined using open field tests (OFT). And the protein expressions and their mRNAs transcription related with APP catabolism were studied using enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR).
RESULTSThe expressions of APP, β-site APP cleaving enzyme 1 (BACE1) and presenilin-1 (PS1) proteins and their mRNAs transcription increased gradually with the increase of Al(mal)3 doses (P<0.05). The enzyme activity of BACE1 in the 0.54 and 1.08 mg/kg Al(mal)3 groups increased significantly (P<0.05). The expression of β-amyloid protein (Aβ) 1-40 gradually decreased while the protein expression of Aβ1-42 increased gradually with the increase of Al(mal)3 doses (P<0.05).
CONCLUSIONResult from our study suggested that one of the possible mechanisms that Al(mal)3 can cause neurotoxicity is that Al(mal)3 can increase the generation of Aβ1-42 by facilitating the expressions of APP, β-, and γ-secretase.
Amyloidogenic Proteins ; genetics ; metabolism ; Animals ; Drug Administration Schedule ; Environmental Pollutants ; administration & dosage ; toxicity ; Gene Expression Regulation ; drug effects ; Male ; Organometallic Compounds ; administration & dosage ; toxicity ; Pyrones ; administration & dosage ; toxicity ; Random Allocation ; Rats ; Rats, Sprague-Dawley