Search Results (220)

ELK1 is a Transcription factor (TF) belonging to the ETS-domain TF family, mainly activated via RAS-RAF-MEK-ERK signaling. As a nethermost pathway molecule, ELK1 binds to Serum-response elements (SREs) and directly regulates the transcription of Immediate early genes (IEGs) including FOS and EGR1. Due to ELK1’s influence on key cellular processes such as proliferation, migration, apoptosis evasion, and Epithelial-to-mesenchymal transition (EMT), its role as a key contributor to tumorigenesis is emerging. In recent years, elevated expression and/or activation of ELK1 has been reported in various malignancies, including lung, breast, prostate, colorectal, blood, gastric, liver, cervical, thyroid and ovarian cancer. ELK1 acts primarily through direct DNA binding but also through interaction with other oncogenes, noncoding RNA molecules, TFs, and upstream kinases (other than ERK1/2), thus participating in diverse axes of transcriptional regulation. Its crucial role in IEG expression has been particularly implicated in cancer progression, metastasis, and drug resistance. Owing to its role in multiple cellular functions and its subsequent oncogenic potential, further elucidation of intracellular ELK1 interactions is of paramount importance. This review aims to summarize current evidence on ELK1’s involvement in solid tumors, dissect reported mechanistic roles, and highlight recent insights that could fuel future ventures of high translational interest. Full article

Background/Objectives: Sweet potato is a tropical and subtropical crop and its growth and yield are susceptible to low-temperature stress. However, the molecular mechanisms underlying the low temperature stress of sweetpotato are unknown. Methods: In this work, combined transcriptome and metabolism analysis was employed to investigate the low-temperature responses of two sweet potato cultivars, namely, the low-temperature-resistant cultivar “X33” and the low-temperature-sensitive cultivar “W7”. Results: The differentially expressed metabolites (DEMs) of X33 at different time stages clustered in five profiles, while they clustered in four profiles of W7 with significant differences. Differentially expressed genes (DEGs) in X33 and W7 at different time points clustered in five profiles. More DEGs exhibited continuous or persistent positive responses to low-temperature stress in X33 than in W7. There were 1918 continuously upregulated genes and 6410 persistent upregulated genes in X33, whereas 1781 and 5804 were found in W7, respectively. Core genes involved in Ca²⁺ signaling, MAPK cascades, the reactive oxygen species (ROS) signaling pathway, and transcription factor families (including bHLH, NAC, and WRKY) may play significant roles in response to low temperature in sweet potato. Thirty-one common differentially expressed metabolites (DEMs) were identified in the two cultivars in response to low temperature. The KEGG analysis of these common DEMs mainly belonged to isoquinoline alkaloid biosynthesis, phosphonate and phosphinate metabolism, flavonoid biosynthesis, cysteine and methionine metabolism, glycine, serine, and threonine metabolism, ABC transporters, and glycerophospholipid metabolism. Five DEMs with identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were selected for correlation analysis. KEGG enrichment analysis showed that the carbohydrate metabolism, phenylpropanoid metabolism, and glutathione metabolism pathways were significantly enriched and played vital roles in low-temperature resistance in sweet potato. Conclusions: These findings contribute to a deeper understanding of the molecular mechanisms underlying plant cold tolerance and offer targets for molecular breeding efforts to enhance low-temperature resistance. Full article

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies. Full article

Transcription factors (TFs) are proteins that control gene expression by binding to specific DNA sequences and are essential for cell development, differentiation, and homeostasis. Dysregulation of TFs is implicated in numerous diseases, including cancer, autoimmune disorders, and neurodegeneration. While TFs were traditionally considered “undruggable” due to their lack of well-defined binding pockets, recent advances have made it possible to modulate their activity using diverse pharmacological strategies. Major TF families include NF-κB, p53, STATs, HIF-1α, AP-1, Nrf2, and nuclear hormone receptors, which take part in the regulation of inflammation, tumor suppression, cytokine signaling, hypoxia and stress response, oxidative stress, and hormonal response, respectively. TFs can perform multiple functions, participating in the regulation of opposing processes depending on the context. NF-κB, for instance, plays dual roles in immunity and cancer, and is targeted by proteasome and IKKβ inhibitors. p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat. STATs, especially STAT3 and STAT5, are oncogenic and targeted via JAK inhibitors or novel PROTAC degraders, for instance SD-36. AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK. Nrf2, a key antioxidant regulator, can be activated by agents like DMF or inhibited in chemoresistant tumors. Pharmacological strategies include direct inhibitors, activators, PROTACs, molecular glues, and epigenetic modulators. Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential. Full article

Foxtail millet (Setaria italica), a significant C4 model crop known for its exceptional photosynthetic efficiency and robust environmental adaptability, serves as an excellent model for investigating C4 photosynthesis and crop stress resilience. When subjected to abiotic stress, foxtail millet employs a sophisticated signal transduction network to regulate its physiological processes, ensuring sustained high photosynthetic efficiency and normal growth. The mitogen-activated protein kinase (MAPK) family plays a key role in plant growth, development, and stress response. Here, we identified and named a MAPK in S. italica as SiMPK6. Fluorescence quantitative PCR analysis revealed that SiMPK6 is mainly expressed in the leaves during the early shooting stage, with induction under various abiotic stresses such as low temperature, high osmotic pressure, high salt, high temperature, and high light. Overexpressing the SiMPK6 in Arabidopsis thaliana mitigated damage to photosystem II induced by stress, underscoring the gene’s crucial role in foxtail millet’s stress signal transduction and maintenance of high photosynthetic efficiency. Full article

Background: Protein Phosphatase 2C (PP2C), a conserved family in plants, plays a crucial role in ABA and MAPK signaling pathways. Its functional diversity provides key mechanisms for plants’ adaptation to environmental changes. However, research on PP2C family members remains significantly underexplored in seagrasses, which are model organisms adapted to complex marine environments. Methods: In this study, we systematically analyzed the PP2C gene family in eelgrass using bioinformatic methods and performed a qPCR experiment to verify the expression of a few members in their response to salt stress. Results: The eelgrass PP2C gene family comprises 52 members, categorized into 13 subfamilies. Most PP2C genes exhibit a differential expression across various organs, with some members showing significant organ specificity. For instance, 12 members are specifically highly expressed in male flowers, suggesting that PP2Cs may function in male flower development. Additionally, four members (ZosmaPP2C-04, ZosmaPP2C-07, ZosmaPP2C-15, and ZosmaPP2C-18) in eelgrass are up-regulated under salt stress, with a qPCR confirming their response. The syntenic genes of ZosmaPP2C-15 and ZosmaPP2C-18 were identified across multiple species, indicating their evolutionary conservation. Numerous response elements associated with plant hormones and stress were identified within the promoter sequences of eelgrass PP2C genes. Notably, the promoter regions of salt-responsive genes are rich in the ABRE, implying that ABA may participate in regulating the expression of these PP2Cs. Furthermore, the predictive analysis of protein interactions suggests the potential existence of the ABA core signaling module PYL-PP2C-SnRK2 in eelgrass. Conclusions: This study provides a new insight for understanding the biological functions of the PP2C family in eelgrass, which is important for elucidating the mechanisms of its growth, development, and environmental adaptability. Full article

Background/Objectives: Desiccation profoundly influences the distribution and abundance of intertidal seaweeds, necessitating robust molecular adaptations. Sargassum muticum is a brown seaweed inhabiting intertidal rocky substrates. During low tides, this species undergoes periodic aerial exposure. Such environmental conditions necessitate robust physiological mechanisms to mitigate desiccation stress. Yet, the molecular basis of this adaptation remains poorly understood. Methods: To investigate desiccation-responsive genes and elucidate the underlying mechanisms of adaptation, we exposed S. muticum to 6 h of controlled desiccation stress in sterilized ceramic trays, simulating natural tidal conditions, and performed comparative transcriptome analysis using RNA-seq on the Illumina NovaSeq 6000 platform. Results: High-quality sequencing identified 66,192 unigenes, with 1990 differentially expressed genes (1399 upregulated and 591 downregulated). These differentially expressed genes (DEGs) were categorized into regulatory genes—including mitogen-activated protein kinase (MAPK), calmodulin, elongation factor, and serine/threonine-protein kinase—and functional genes, such as heat shock protein family members (HSP20, HSP40, and HSP70), tubulin (TUBA and TUBB), and endoplasmic reticulum homeostasis-related genes (protein disulfide-isomerase A6, calreticulin, and calnexin). Gene Ontology (GO) enrichment highlighted upregulated DEGs in metabolic processes like glutathione metabolism, critical for oxidative stress mitigation, while downregulated genes were linked to transport functions, such as ammonium transport, suggesting reduced nutrient uptake during dehydration. KEGG pathway analysis revealed significant enrichment in “protein processing in endoplasmic reticulum” and “MAPK signaling pathway-plant”, implicating endoplasmic reticulum stress response and conserved signaling cascades in desiccation adaptation. Validation via qRT-PCR confirmed consistent expression trends for key genes, reinforcing the reliability of transcriptomic data. Conclusions: These findings suggest that S. muticum undergoes extensive biological adjustments to mitigate desiccation stress, highlighting candidate pathways for future investigations into recovery and tolerance mechanisms. Full article

In eukaryotes, the mitogen-activated protein kinase (MAPK) cascade pathway is a highly conserved cell signaling mechanism that is essential for stress response, growth, and development. MAPK cascade genes have currently been identified and characterized in a wide range of fungi, although they have not been fully understood in early divergent fungal lineages like the Mucoromycota, which contains Mucoromycotina, Glomeromycotina, and Mortierellomycotina. In this study, a genome-wide investigation of Blakeslea trispora (Mucorales, Choanephoraceae) revealed a total of 19 MAPK cascade genes, including 9 BtMAPKKKs, 4 BtMAPKKs, and 6 BtMAPKs genes. Using phylogenetic analysis, it was found that the kinase domain sequences and motif composition of the three MAPK, MAPKK, and MAPKKK lineages are substantially conserved in fungi. Whole genome duplication analysis indicated that B. trispora has four and nine duplication pairs in the MAPK and MAPKKK genes, respectively, which are expanded by segmental replication events. BtHog2, the orthologous protein of Hog1, exhibits a substantial rise in transcription levels under blue light irradiation, indicating its function in light signal response and transduction. Several sets of interacting protein pairs were found using molecular docking analysis and yeast two-hybrid assay, providing a comprehensive MAPK cascade signaling network in B. trispore. Furthermore, MAPK cascade proteins show varying transcription levels in response to blue light and sex hormone stimulation, as well as variable treatment duration. BtMAPKKK9 and BtBck1 are strongly induced during sexual interaction, indicating their involvement in the response to trisporic acid and the subsequent alterations in hyphal cell wall structure. These findings shed light on the evolution of MAPK cascade genes and the functional mechanisms underlying MAPK cascade genes in response to light and sex hormone signaling pathways in B. trispore. Full article

With the continuous change of climate, drought stress has emerged as the primary constraint on crop growth, posing a significant threat to the stability of global grain reserves. Arbuscular mycorrhizal fungi (AMF), as a kind of widely distributed root endophytes, enhance the drought tolerance of maize (Zea mays L.) through regulating the physiological and molecular responses. However, comprehensive transcriptome analysis to reveal the molecular mechanism of drought tolerance in the symbiotic process between AMF and maize is still limited. In the potted plant experiment, maizes inoculated with and without arbuscular mycorrhizal fungus Funneliformis mosseae were grown under well-watered (WW) or drought-stressed (DS) conditions. By using RNA-Seq and transcriptome analysis on maize roots and leaves, this work aimed to investigate the differential expressed genes (DEGs) related to the Ca²⁺ signaling pathway induced by AMF symbiosis under drought stress. Our findings indicated that F. mosseae inoculation resulted in a decrease in the net fluxes of Ca²⁺, while simultaneously elevating Ca²⁺ contents in the maize roots and leaves under well-watered or drought-stressed conditions. Notably, 189 DEGs were regulated not only by AMF symbiosis and drought stress, but also exhibited preferential expression in either leaves or roots. The annotation and enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that most of the DEGs were significantly enriched in Ca²⁺ signaling pathway genes, related to signal transduction, cellular process, and defense response. A high number of DEGs with this function (including calcineurin B-like protein (CBL), CBL-interacting protein kinase (CIPK), mitogen-activated protein kinase (MAPK), and calcium-dependent protein kinase (CDPK) receptor kinases) were upregulated-DEGs or downregulated-DEGs in F. mosseae-inoculated maizes under drought stress. Furthermore, some DEGs belong to transcription factor (TF) families, including bHLH ERF, and, MYB, were speculated to play key roles in improving the drought tolerance of maize. Based on the expression data and co-expression analysis between TF and Ca²⁺ signaling pathway genes, Whirly1 with CBL11, and BRI1-EMS-SUPPRESSOR 1 (BES1) with CBL10, CIPK24, CDPK1, CDPK14, CDPK19, and MAPK9 genes showed significant positive correlations, while B3 domain-containing transcription factors (B3 TFs) with MAPK1 and both CBL9 genes showed significant negative correlations in response to both F. mosseae inoculation and drought stress. The regulation of Ca²⁺ signaling pathways by AMF symbiosis was an important response mechanism of maize to improve their drought resistance. This study provides insightful perspectives on how AMF-induced modulation of gene expression within the Ca²⁺ signaling pathway can enhance the drought tolerance of mycorrhizal maize in the future. Full article

Bamboo is a member of the Poaceae family and serves as an important economic resource with various applications, including reforestation, food production, and environmental conservation, due to its rapid growth and renewable nature. Among its various uses, bamboo shoots stand out for their tender texture and delicate flavor, making them a highly sought-after culinary delicacy in many cultures and a key ingredient in global food industries. Despite extensive research on the development of monopodial bamboos, studies focused on the developmental processes of sympodial bamboos, especially regarding their culinary potential, remain limited. This study conducted a comprehensive transcriptomic analysis of sympodial bamboo (Bambusa sp.) across six developmental stages (S1–S6) to uncover the molecular regulatory networks governing early bamboo shoot development. The results revealed that 1603 common differentially expressed genes (DEGs) across S1–S6 were enriched in multiple key pathways, with the most significant being plant hormone signaling, MAPK signaling, and Glycolysis/Gluconeogenesis pathways. Co-expression clustering analysis indicated that the Glycolysis/Gluconeogenesis pathway plays a crucial role during the later stages of bamboo shoot development (S5–S6), impacting its texture and flavor—two critical factors determining its culinary quality. Further Weighted Gene Co-expression Network Analysis (WGCNA) highlighted the significant role of the MAPK signaling pathway during early bamboo shoot development and identified key hub genes (MKK, MPK, MEKK) within this pathway, emphasizing their importance in cell division and hormonal coordination. This study provides valuable insights into the molecular mechanisms underlying the rapid growth and exceptional flavor of bamboo shoots and lays the foundation for the genetic improvement of bamboo as a sustainable and nutritious food source, enhancing its value as a premium food ingredient in the global market. Full article

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. These lesions are the result of the aberrant cell signaling step proteins, which normally regulate cell proliferation. Mitogen-activated protein kinase (MAPK) pathways and tyrosine kinase receptors are involved in tumorigenesis of low-grade gliomas. High-grade gliomas may carry similar mutations, but loss of epigenetic control is the dominant molecular event; it can occur either due to histone mutations or inappropriate binding or unbinding of DNA on histones. Therefore, despite the absence of genetic alteration in the classic oncogenes or tumor suppressor genes, uncontrolled transcription results in tumorigenesis. Isocitric dehydrogenase (IDH) mutations do not predominate compared to their adult counterpart. Embryonic tumors include medulloblastomas, which bear mutations of transcription-regulating pathways, such as wingless-related integration sites or sonic hedgehog pathways. They may also relate to high expression of Myc family genes. Atypical teratoid rhabdoid tumors harbor alterations of molecules that contribute to ATP hydrolysis of chromatin. Embryonic tumors with multilayered rosettes are associated with microRNA mutations and impaired translation. Ependymomas exhibit great variability. As far as supratentorial lesions are concerned, the major events are mutations either of NFkB or Hippo pathways. Posterior fossa tumors are further divided into two types with different prognoses. Type A group is associated with mutations of DNA damage repair molecules. Lastly, germ cell tumors are a heterogeneous group. Among them, germinomas manifest KIT receptor mutations, a subgroup of the tyrosine kinase receptor family. Full article

The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl₂) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNFα and IL-1β. CoCl₂ exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-κB/NLRP3. These responses were significantly mitigated by treatment with anti-TNFα and anti-IL-1β, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl₂ exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNFα and anti-IL-1β treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets. Full article

Low temperature stress represents a significant abiotic stress factor affecting rice yields. While the structure and some of the functions of cell cycle protein-dependent protein kinase inhibitor (CKI) family proteins have been the subject of study, their relevance to cold tolerance in rice has been less investigated. In this study, we cloned OsEL2 (LOC_Os03g01740) and constructed anti-expression lines of this gene. The resulting lines exhibited significant cold sensitivity and displayed greater oxidative damage than wild type Nippobare (Nip). However, the activities of antioxidant enzymes, such as catalase (CAT), were significantly elevated in OsEL2-AX plants in comparison to Nip following exposure to 4 °C stress. RNA sequencing revealed the presence of 18,822 differential genes, with the majority of them being expressed with temporal specificity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that a considerable number of differentially expressed genes (DEGs) are involved in the metabolism of amino acids, lipids, and terpenoids. Weighted gene co-expression network analysis (WGCNA) revealed a close relationship between the genes in the turquoise and light green modules and rice cold tolerance traits. These genes were predominantly enriched in terpene metabolism and the metabolism of various plant secondary metabolites, suggesting that OsEL2 influences rice cold tolerance through the metabolism of these two classes of substances. An analysis of the genes within these two modules using transcription factor (TF) enrichment and KEGG enrichment revealed that they are predominantly regulated by mitogen-activated protein kinase (MAPK) and ethylene signaling pathways. Furthermore, we found that tryptophan metabolism, phenylalanine metabolism, and monoterpene synthesis were enriched in down-regulated pathway enrichment analysis. In addition, we also found that the MAPK signaling pathway was enriched in the KEGG enrichment analysis of AX2 with Nip. The results demonstrate that anti-expression of OsEL2 is associated with a notable decline in rice tolerance to cold stress. Full article

Background: Aberrant expression and mutations in the fibroblast growth factor (FGF) family play crucial roles in cell differentiation, growth, and migration, contributing to tumor progression across various cancers. Nasopharyngeal carcinoma (NPC), a malignancy prevalent in East Asia, is primarily treated with radiotherapy; however, radioresistance remains a major challenge, leading to recurrence and poor outcomes. While FGFs are known to activate signaling pathways such as MAPK, PI3K/AKT, and JAK/STAT to promote cancer progression, the specific role of individual FGFs in NPC radioresistance remains unclear. Emerging evidence highlights FGF5 as a key player in NPC progression, metastasis, and radioresistance, underscoring its potential as a therapeutic target to overcome treatment resistance and improve clinical outcomes. Methods: We analyzed single nucleotide variation (SNV) data, gene expression, and DNA methylation patterns using cancer datasets, including TCGA and GTEx, to investigate FGF5 expression. Differentially expressed genes (DEGs) were identified and interpreted using functional enrichment analysis, while survival analysis and gene set enrichment analysis (GSEA) were conducted to identify clinical correlations. DNA methylation patterns were specifically assessed using the HumanMethylation850 BeadChips on tissue samples from nine recurrent and nine non-recurrent NPC patients. Functional assays, including cell viability, migration, invasion, and clonogenic survival assays, were performed to evaluate the effects of FGF5 on NPC cell behavior in vitro and in vivo. Results: FGF5 showed elevated SNV frequencies across multiple cancers, particularly in HNSC and NPC. DNA methylation analysis revealed an inverse relationship between FGF5 expression and methylation levels in recurrent NPC tumors. Functional assays demonstrated that FGF5 enhances migration, invasion, and radioresistance in NPC cells. High FGF5 expression was associated with reduced distant metastasis-free survival (DMFS) and increased radioresistance, highlighting its role in metastatic progression and recurrence. Conclusions: FGF5 plays a significant role in the progression and recurrence of nasopharyngeal carcinoma. Its elevated expression correlates with increased migration, invasion, and radioresistance as well as reduced distant metastasis-free survival. These findings suggest that FGF5 contributes to the metastatic and recurrence potential of NPC, making it a potential target for therapeutic intervention in treating these cancers. Full article

Parkinson’s disease (PD) is characterized by widespread distribution of Lewy bodies, which are composed of phosphorylated and aggregated forms of α-Synuclein (α-Syn), in the brain. Although the accumulation and propagation of α-Syn contribute to the development of PD, the involvement of the blood–brain barrier (BBB) in these processes remains unknown. Pericytes, one of the cell types that constitute the BBB, degrade various forms of α-Syn. However, the detailed mechanisms involved in α-Syn degradation by pericytes remain poorly understood. Therefore, in this study, we aimed to determine the ability of the BBB-constituting cells, particularly primary cultures of rat pericytes, brain endothelial cells, and astrocytes, to degrade α-Syn. After α-Syn uptake by the cells, intracellular α-Syn decreased only in pericytes. This pericyte-specific α-Syn decrease was inhibited by an autophagy inhibitor, bafilomycin A1, and a proteasome inhibitor, MG132. siRNA-mediated knockdown of degradation enzymes or familial PD-associated genes, including cathepsin D, DJ-1, and LRRK2, did not affect α-Syn clearance in pericytes. However, pharmacological inhibitors of Akt, ERK, and p38 MAPK inhibited α-Syn degradation by pericytes. In conclusion, our results suggest that α-Syn degradation by pericytes is mediated by an autophagy–lysosome system and a ubiquitin–proteasome system via α-Syn-activated Akt, ERK, and p38 MAPK signaling pathways. Full article