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1.
J Phys Chem B ; 126(20): 3648-3658, 2022 05 26.
Article in English | MEDLINE | ID: covidwho-1947182

ABSTRACT

Aggregates of α-synuclein are thought to be the disease-causing agent in Parkinson's disease. Various case studies have hinted at a correlation between COVID-19 and the onset of Parkinson's disease. For this reason, we use molecular dynamics simulations to study whether amyloidogenic regions in SARS-COV-2 proteins can initiate and modulate aggregation of α-synuclein. As an example, we choose the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the envelope protein of SARS-COV-2. We probe how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs. We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only a small effect on the stability of pre-existing or newly formed fibrils. A potential mechanism and key residues for potential virus-induced amyloid formation are described.


Subject(s)
Amyloidogenic Proteins , Coronavirus Envelope Proteins , Parkinson Disease , Peptide Fragments , alpha-Synuclein , Amyloidogenic Proteins/chemistry , Amyloidogenic Proteins/metabolism , COVID-19/virology , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Humans , Parkinson Disease/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , SARS-CoV-2/metabolism , alpha-Synuclein/chemistry , alpha-Synuclein/metabolism
2.
Protein Cell ; 13(8): 602-614, 2022 08.
Article in English | MEDLINE | ID: covidwho-1777862

ABSTRACT

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.


Subject(s)
Amyotrophic Lateral Sclerosis , COVID-19 , Amyloidogenic Proteins/metabolism , Amyotrophic Lateral Sclerosis/genetics , Animals , Cytoplasmic Granules/metabolism , Mammals , SARS-CoV-2 , Stress Granules
3.
Diagn Microbiol Infect Dis ; 99(2): 115169, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1064997

ABSTRACT

We evaluated simple laboratory variables to discriminate COVID-19 from bacterial pneumonia or influenza and for the prospective grading of COVID-19. Multivariate logistic regression and receiver operating characteristic curve were used to estimate the diagnostic performance of the significant discriminating variables. A comparative analysis was performed with different severity. The leukocytosis (P = 0.017) and eosinopenia (P = 0.001) were discriminating variables between COVID-19 and bacterial pneumonia with area under the curve (AUC) of 0.778 and 0.825. Monocytosis (P = 0.003), the decreased lymphocyte-to-monocyte ratio (P < 0.001), and the increased neutrophil-to-lymphocyte ratio (NLR) (P = 0.028) were predictive of influenza with AUC of 0.723, 0.895, and 0.783, respectively. Serum amyloid protein, lactate dehydrogenase, CD3+ cells, and the fibrinogen degradation products had a good correlation with the severity of COVID-19 graded by age (≥50) and NLR (≥3.13). Simple laboratory variables are helpful for rapid diagnosis on admission and hierarchical management of COVID-19 patients.


Subject(s)
COVID-19/diagnosis , Influenza, Human/diagnosis , Pneumonia, Bacterial/diagnosis , Severity of Illness Index , Adolescent , Adult , Amyloidogenic Proteins/blood , Child , Child, Preschool , Diagnosis, Differential , Eosinophilia/pathology , Female , Fibrinogen/metabolism , Humans , L-Lactate Dehydrogenase/blood , Leukocytosis/pathology , Lymphocyte Count , Male , Middle Aged , Monocytes/cytology , Neutrophils/cytology , Retrospective Studies , SARS-CoV-2 , Young Adult
4.
Int J Mol Sci ; 21(24)2020 Dec 15.
Article in English | MEDLINE | ID: covidwho-977756

ABSTRACT

At present, much attention is paid to the use of antimicrobial peptides (AMPs) of natural and artificial origin to combat pathogens. AMPs have several points that determine their biological activity. We analyzed the structural properties of AMPs, as well as described their mechanism of action and impact on pathogenic bacteria and viruses. Recently published data on the development of new AMP drugs based on a combination of molecular design and genetic engineering approaches are presented. In this article, we have focused on information on the amyloidogenic properties of AMP. This review examines AMP development strategies from the perspective of the current high prevalence of antibiotic-resistant bacteria, and the potential prospects and challenges of using AMPs against infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Subject(s)
Amyloidogenic Proteins/pharmacology , COVID-19/drug therapy , COVID-19/virology , Pore Forming Cytotoxic Proteins/pharmacology , SARS-CoV-2/drug effects , Amyloidogenic Proteins/adverse effects , Amyloidogenic Proteins/therapeutic use , Animals , Coronavirus Infections/drug therapy , Humans , Pore Forming Cytotoxic Proteins/adverse effects , Pore Forming Cytotoxic Proteins/therapeutic use , Proteome
5.
Amyloid ; 27(4): 217-222, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-889371

ABSTRACT

The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' in vivo amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.


Subject(s)
Amyloid/classification , Amyloidogenic Proteins/classification , Amyloidosis/classification , Terminology as Topic , Amyloid/genetics , Amyloid/metabolism , Amyloidogenic Proteins/genetics , Amyloidogenic Proteins/metabolism , Amyloidosis/diagnosis , Amyloidosis/genetics , Amyloidosis/pathology , COVID-19 , Congresses as Topic , Coronavirus Infections , Education, Distance/organization & administration , Gene Expression , Humans , Pandemics , Pneumonia, Viral
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