https://www.frontiersin.org/articles/10.3389/fgene.2021.741175/full
Identifying New COVID-19 Receptor Neuropilin-1 in Severe Alzheimer’s Disease Patients Group Brain Using Genome-Wide Association Study Approach
Key-Hwan Lim†, 
Sumin Yang- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, South Korea
Recent preclinical studies show that Neuropilin-1 (NRP1), which is a transmembrane protein with roles in neuronal development, axonal outgrowth, and angiogenesis, also plays a role in the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, we hypothesize that NRP1 may be upregulated in Alzheimer’s disease (AD) patients and that a correlation between AD and SARS-CoV-2 NRP1-mediated infectivity may exist as angiotensin converting enzyme 2 (ACE2). We used an AD mouse model that mimics AD and performed high-throughput total RNA-seq with brain tissue and whole blood. For quantification of NRP1 in AD, brain tissues and blood were subjected to Western blotting and real-time quantitative PCR (RT-qPCR) analysis. In silico analysis for NRP1 expression in AD patients has been performed on human hippocampus data sets. Many cases of severe symptoms of COVID-19 are concentrated in an elderly group with complications such as diabetes, degenerative disease, and brain disorders. Total RNA-seq analysis showed that the Nrp1 gene was commonly overexpressed in the AD model. Similar to ACE2, the NRP1 protein is also strongly expressed in AD brain tissues. Interestingly, in silico analysis revealed that the level of expression for NRP1 was distinct at age and AD progression. Given that NRP1 is highly expressed in AD, it is important to understand and predict that NRP1 may be a risk factor for SARS-CoV-2 infection in AD patients. This supports the development of potential therapeutic drugs to reduce SARS-CoV-2 transmission.
Sitaatti:
Angiotensin converting enzyme 2 (ACE2) is required for SARS-CoV-2 infection. Recently, it is reported that the Ace2 gene and protein expression are elevated in AD patients compared with in normal elderly individuals (Ding et al., 2020; Lim et al., 2020; Rahman et al., 2020). Consistent with these results, an increase in ACE2 expression results in an increased susceptibility to SARS-CoV-2 infection in elderly patients with AD.
Furthermore, a recent study suggests that the transmembrane protein Neuropilin-1 (NRP1) also plays a role in SARS-CoV-2 infection (Daly et al., 2020; Mayi et al., 2021). Biochemical experiments and X-ray crystallography show that NRP1 strongly interacts with a polybasic sequence on the spike protein of SARS-CoV-2, which fits the C-end rule region (CendR) required for NRP1-peptide interaction (Daly et al., 2020; Song et al., 2020).
NRP1 depletion with RNAi targeting Nrp1 mRNA inhibits the binding of the SARS-CoV-2 spike protein to NRP1 and, consequently, decreases the rate of viral infection (Daly et al., 2020; Song et al., 2020). In addition, a monoclonal antibody against the b1b2 domain of NRP1 reduces the infectivity of SARS-CoV-2 lentiviral pseudo-particles (Cantuti-Castelvetri et al., 2020). NRP1 is a neuronal receptor associated with the regulation of neurite outgrowth through the binding of vascular endothelial growth factor (VEGF) (Abdullah et al., 2020).
When NRP1 is activated by CendR, which is a peptide R/KXXR/K motif contained within C-terminal domains, it enables cells to internalize ligands, such as viruses, containing the motif (Teesalu et al., 2009). Furthermore, NRP1 is expressed in the central nervous system, including the brain olfactory-related regions in which SARS-CoV-2 entry may occur, thereby facilitating COVID-19 infection (Davies et al., 2020).
Thus, we hypothesize that, in addition to ACE2, NRP1 expression might be upregulated in the brains of elderly AD patients. In this study, molecular characterization via high-throughput analysis and biochemical assays reveals that NRP1 is highly expressed in AD, which suggests that NRP1 may be a potential genetic therapy target in AD patients with COVID-19.
(Neuropiilien rakenne)
Entrez Gene Summary for NRP1 Gene
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This gene encodes one of two neuropilins, which contain specific protein domains which allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contains a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors; they affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members.
This protein has also been determined to act as a co-receptor for SARS-CoV-2 (which causes COVID-19) to infect host cells. [provided by RefSeq, Nov 2020]
GeneCards Summary for NRP1 Gene
NRP1 (Neuropilin 1) is a Protein Coding gene. Diseases associated with NRP1 include Covid-19 and Cerebral Arteriopathy, Autosomal Dominant, With Subcortical Infarcts And Leukoencephalopathy, Type 1. Among its related pathways are Development Slit-Robo signaling and p70S6K Signaling. Gene Ontology (GO) annotations related to this gene include heparin binding and growth factor binding. An important paralog of this gene is NRP2.
UniProtKB/Swiss-Prot Summary for NRP1 Gene
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Cell-surface receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. Mediates the chemorepulsant activity of semaphorins (PubMed:9288753, PubMed:9529250, PubMed:10688880). Recognizes a C-end rule (CendR) motif R/KXXR/K on its ligands which causes cellular internalization and vascular leakage (PubMed:19805273). It binds to semaphorin 3A, the PLGF-2 isoform of PGF, the VEGF165 isoform of VEGFA and VEGFB (PubMed:9288753, PubMed:9529250, PubMed:10688880, PubMed:19805273). Coexpression with KDR results in increased VEGF165 binding to KDR as well as increased chemotaxis. Regulates VEGF-induced angiogenesis. Binding to VEGFA initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). Regulates mitochondrial iron transport via interaction with ABCB8/MITOSUR (PubMed:30623799).
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[Isoform 2]: Binds VEGF-165 and may inhibit its binding to cells (PubMed:10748121, PubMed:26503042). May induce apoptosis by sequestering VEGF-165 (PubMed:10748121). May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity.
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(Microbial infection) Acts as a host factor for human coronavirus SARS-CoV-2 infection. Recognizes and binds to CendR motif RRAR on SARS-CoV-2 spike protein S1 which enhances SARS-CoV-2 infection.
Gene Wiki entry for NRP1 Gene
NRP1, (10p11.22.), 922 aminoacids.
Protein attributes for NRP1 Gene
- Size:
- 923 amino acids
- Molecular mass:
- 103134 Da
- Quaternary structure:
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- Homodimer, and heterodimer with NRP2 (PubMed:17989695). Interacts with FER (By similarity). Interacts with PLXNB1 (PubMed:10520995). Interacts with VEGFA (PubMed:26503042, PubMed:19805273). Interacts with ABCB8/MITOSUR in mitochondria (PubMed:30623799).
- (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein S1 (via the CendR motif RRAR).
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