The Human Coronavirus Receptor ANPEP (CD13) Is Overexpressed in Parkinson's Disease

Abstract

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), 1 a new human coronavirus (hCoV) strain. The neuroinvasive potential of SARS-CoV-2 2 and recent research linking advanced age and neurological disease to COVID-19 severity 3 raise concerns for patients with Parkinson's disease (PD), who appear to be particularly susceptible to worse outcomes from COVID-19. 4 Using a combination of publicly available and in-house RNA sequencing (RNAseq) data, we compared the abundance of the SARS-CoV-2 entry factors angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) between PD case and control whole blood (WB), frontal cortex (FC), and substantia nigra (SN) tissues. In addition, similar to others, 5 we expanded our investigation to include other hCoV entry factors, including aminopeptidase N (ANPEP, HCoV-229E), dipeptidyl peptidase 4 (DPP4, MERS-CoV), and glutamyl aminopeptidase (ENPEP), 6 all of which have been discussed as potential SARS-CoV-2 corecepetors. 6 We hypothesized that the expression of hCoV receptor genes in patients with PD differs from that of healthy individuals, potentially explaining the links between COVID-19 and worsened outcomes in PD. In line with available data (Genotype-Tissue Expression project 7), ACE2 was undetectable in WB in all cohorts. No expression was observed in SN tissue in PD cases or control subjects. Low ACE2 expression was observed in FC tissue, but in PD cases and control subjects the difference was not statistically significant (Fig. 1A), suggesting that ACE2 expression levels are not likely to be a significant contributor to the reported COVID-19 susceptibility in PD. 4 TMPRSS2 was also undetectable in WB and either brain tissue. DPP4 and ENPEP, although undetected in WB, may contribute to hCoV neuroinvasion 2 because both are expressed in FC and SN tissue; however, there was no significant difference in transcript abundance between PD cases and control subjects (P > 0.05; data not shown). Finally, we did not detect any significant correlation between genes, and no significant correlation was found between ACE2, DPP4 and ENPEP expression and age in cases or control subjects in any of the tissues examined (P > 0.05). Intriguingly, we saw significantly elevated ANPEP expression (adjusted P < 0.05) in PD cases compared with control subjects in all WB cohorts and FC tissue (Fig. 1B-G), but not in SN tissue (Fig. 1H), although we found no correlation between ANPEP expression and age in PD cases or control

Comprehensive Oncogenic Features of Coronavirus Receptors in Glioblastoma Multiforme

“…Interestingly, ACE2 and TMPRSS2, the two widely accepted receptors in SARS-CoV-2 cell entry, have been reported to be relatively low in endothelial cells of the human brain in two studies ( 52 , 72 ), which is consistent with the results shown in Figure 1 . Nevertheless, the coronavirus receptors ANEPE, AXL, and ENPEP were detected in the olfactory region and endothelial cells of human brain ( Figures 1B and 2C ), indicating that SARS-CoV-2 cell entry in human brain might require these three receptors rather than rely on ACE2 and TMPRSS2.…”

Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort

“…43 Recently, ANPEP was described as a human coronavirus entry factor, 50 showing an important role in Parkinson's disease progression. 51 In our study, two of the ND FTND -specific DMS mapped to ANPEP correlated with methylation in brain tissue (cg06344992 and cg02008229). The last ND FTND -specific gene was SLC29A1, which mediates the uptake of nucleosides and has not been correlated to smoking in previous EWAS.…”

“…Another DMS mapped to the ANPEP is known as a diabetes risk gene, 49 recently identified as smoking‐associated in an EWAS examining the effects of cadmium and smoking in the Strong Heart Study cohort in blood tissue 43 . Recently, ANPEP was described as a human coronavirus entry factor, 50 showing an important role in Parkinson's disease progression 51 . In our study, two of the ND FTND ‐specific DMS mapped to ANPEP correlated with methylation in brain tissue (cg06344992 and cg02008229).…”

Diversity of Coronavirus Receptors

“…The patients with Parkinson's disease (PD) appear to be susceptible to worse outcomes from COVID-19. It is speculated that overexpression of ANP in these patients could be one of the causes for it [176,177].…”