The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinson’s disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in α-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous α-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with α-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS/STAT3/HIF-1α axis. Our research revealed the relationships among α-synuclein, IL6ST, STAT3, and HIF-1α in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD.

Alpha-synuclein (α-Syn) is widely distributed and involved in the regulation of the nervous system. The phosphorylation of α-Syn at serine 129 (p^Ser129α-Syn) is known to be closely associated with α-Synucleinopathies, especially Parkinson's disease (PD). The present study aimed to explore the α-Syn accumulation and its phosphorylation in the enteric nervous system (ENS) in patients without neurodegeneration. Patients who underwent colorectal surgery for either malignant or benign tumors that were not suitable for endoscopic resection (n = 19) were recruited to obtain normal intestinal specimens, which were used to assess α-Syn immunoreactivity patterns using α-Syn and p^Ser129α-Syn antibodies. Furthermore, the sub-location of α-Syn in neurons was identified by α-Syn/neurofilament double staining. Semi-quantitative counting was used to evaluate the expression of α-Syn and p^Ser129α-Syn in the ENS. Positive staining of α-Syn was detected in all intestinal layers in patients with non-neurodegenerative diseases. There was no significant correlation between the distribution of α-Syn and age (p = 0.554) or tumor stage (p = 0.751). Positive staining for p^Ser129α-Syn was only observed in the submucosa and myenteric plexus layers. The accumulation of p^Ser129α-Syn increased with age. In addition, we found that the degenerative changes of the ENS were related to the degree of tumor malignancy (p = 0.022). The deposits of α-Syn were present in the ENS of patients with non-neurodegenerative disorders; particularly the age-dependent expression of p^Ser129α-Syn in the submucosa and myenteric plexus. The current findings of α-Syn immunostaining in the ENS under near non-pathological conditions weaken the basis of using α-Syn pathology as a suitable hallmark to diagnose α-Synucleinopathies including PD. However, our data provided unique perspectives to study gastrointestinal dysfunction in non-neurodegenerative disorders. These findings provide new evidence to elucidate the neuropathological characteristics and α-Syn pathology pattern of the ENS in non-neurodegenerative conditions.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Inflammation, marked by the infiltration of inflammatory mediators and the proliferation of inflammatory cells, is closely linked to PD. This study aims to identify and validate inflammation‐related biomarkers in PD and construct a TF–mRNA–miRNA coexpression network through bioinformatics analysis. Methods: The PD‐associated dataset GSE7621 and inflammation‐related genes were downloaded from the GEO Database and GeneCards platform to obtain inflammation‐related differential expression genes (IRDEGs). The key IRDEGs were generated by PPI network analysis. The gene expression levels of the key IRDEGs were validated by blood samples from PD patients using QPCR analysis. We utilized the ENCODE, hTFtarget, CHEA, miRWALK, and miRDB databases to obtain upstream and downstream molecular network models for constructing the TF–mRNA–miRNA interaction network of the key IRDEGs. Finally, based on CIBERSORT algorithm, the associations between IRDEs and immune cell infiltration were investigated. Results: A total of four key IRDEGs (CXCR4, LEP, SLC18A2, and TAC1) were screened and validated. Through biological function analysis, key‐related pathways and coexpression networks of PD were identified. These genes may be closely related to the onset of PD. Additionally, we found that increased CD4 T‐cell infiltration might be associated with the occurrence of PD. Conclusions: We identified four potential inflammation‐related treatment target and constructed a TF–mRNA–miRNA regulatory network. This information provides an initial basis for understanding the complex PD regulatory mechanisms.

Aims: We aimed to investigate the shared molecular pathways between Parkinson's disease (PD) and constipation using bioinformatics analysis. Methods: Differentially expressed genes (DEGs) were identified via the R limma package, and Weighted Gene Co‐Expression Network Analysis (WGCNA) was conducted to identify hub modules. Biological enrichment analysis clarified the biological processes involved. A gene–gene interaction (GGI) network was constructed to identify shared hub biomarkers. Validation of these biomarkers was done in vitro with α‐synuclein (α‐syn)‐treated SH‐SY5Y cells and in vivo through α‐syn‐induced PD mouse models, A53T transgenic mice, and loperamide‐induced constipation models. Results: Numerous DEGs were identified in both conditions, with 14 shared DEGs found through the intersection of core modules and upregulated DEGs. These DEGs are primarily involved in energy metabolism, protein modification, and mitochondrial function. Five key hub genes were identified using the GGI network and gene topological analysis. Notably, Serine hydroxymethyltransferase 2 (SHMT2) expression was significantly upregulated after α‐syn treatment in vitro. Immunohistochemical and immunofluorescence analyses revealed elevated SHMT2 expression in brain and colon tissues in PD mouse models ( p < 0.001), whereas in constipation models, SHMT2 was only elevated in the colon wall with no significant expression in the enteric nervous system. Conclusion: Our findings offer new views on the molecular link between PD and constipation, suggesting SHMT2 as a possible biomarker and therapeutic target for PD symptoms.