Search Results (223)

Neonatal Diabetes Mellitus (NDM) is a rare, heterogeneous monogenic disorder typically presenting within the first six months of life. Unlike type 1 or type 2 diabetes, NDM is caused by single-gene mutations that disrupt pancreatic β-cell function or development. With the advent of next-generation sequencing, the genetic spectrum of NDM has expanded significantly, necessitating a shift from symptomatic management to precision medicine. This narrative review summarizes the genetic basis and pathogenic mechanisms of NDM, categorizing them into three major pathways: (1) ATP-sensitive potassium (K_ATP) channelopathies (e.g., ABCC8, KCNJ11), where gain-of-function mutations inhibit insulin secretion; (2) Transcription factor defects (e.g., GLIS3, PAX6, GATA6), which impair pancreatic development and often present with syndromic features; and (3) Endoplasmic reticulum (ER) stress-mediated β-cell apoptosis, exemplified by WFS1 mutations. Furthermore, we highlight the clinical complexity of these mutations, including the “biphasic phenotype” observed in ABCC8 and HNF1A variants. Understanding these molecular mechanisms is critical for clinical decision-making. We discuss the transformative impact of genetic diagnosis in treatment, particularly the successful transition from insulin to oral sulfonylureas in patients with K_ATP channel mutations, and emphasize the importance of early genetic testing to optimize glycemic control and prevent complications. Full article

Objective: To investigate the mechanism by which sphingosine-1-phosphatase 2 (SGPP2) modulates endoplasmic reticulum stress (ERS) through the SIRT1/AMPK pathway to improve ischemic cardiomyopathy-induced chronic heart failure (IHF). Methods: Key genes of IHF and ERS were identified through bioinformatics analysis, and significantly associated pathways of the key genes were obtained via single-gene enrichment analysis. In vivo, IHF was induced in Sprague–Dawley (male) rats via ligation of the left anterior descending coronary artery, with cardiac function examined through echocardiography. Myocardial tissue injury and fibrosis were evaluated utilizing hematoxylin-eosin, Masson, and TUNEL staining. Serum levels of NT-proBNP and cTnT were measured via ELISA. SGPP2 protein expression was assessed via immunohistochemistry and Western blotting (WB). In vitro, neonatal rat cardiomyocytes (NRCMs) were isolated and underwent oxygen-glucose deprivation (OGD) to establish an IHF model. SGPP2-overexpressing NRCMs were constructed and treated with the ERS inducer tunicamycin (Tu) or the SIRT1 inhibitor EX527. Cell injury was evaluated using Cell Counting Kit-8 and lactate dehydrogenase release assays, as well as flow cytometry. Endoplasmic reticulum structure was examined by transmission electron microscopy. The endoplasmic reticulum was labeled with the ER-Tracker Red molecular probe. WB was utilized to detect the expression of apoptosis- and ERS-linked proteins, and the activity of the SIRT1/AMPK signaling pathway. Results: Six key genes (CTSK, FURIN, SLC2A1, RSAD2, SGPP2, and STAT3) were identified through bioinformatics analysis, with SGPP2 showing the most significant differential expression. Additionally, SGPP2 was found to be downregulated in IHF. Single-gene enrichment analysis showed that SGPP2 exhibited a significant association with the AMPK signaling pathway. Animal experiments demonstrated that rats with IHF exhibited significantly impaired cardiac function, marked myocardial tissue injury and fibrosis, ERS in myocardial tissue, lowered SGPP2 expression, and decreased SIRT1/AMPK signaling pathway activity. In vitro experiments confirmed that SGPP2 overexpression alleviated OGD-induced cardiomyocyte injury by inhibiting ERS and simultaneously activating the SIRT1/AMPK signaling pathway. Rescue experiments further demonstrated that both Tu and EX527 significantly promoted ERS and cellular injury, thereby counteracting the protective effects of SGPP2. Conclusions: SGPP2 alleviates IHF by inhibiting ERS modulated by the SIRT1/AMPK pathway. Full article

The synthesis of the melanin pigment in melanocytes plays a crucial role in protecting the body from ultraviolet radiation. Tyrosinase, a key enzyme in melanogenesis, catalyzes the conversion of tyrosine to melanin in the melanosomes of melanocytes. During melanogenesis, Tyrosinase is abundantly synthesized in the lumen of the endoplasmic reticulum (ER) and subsequently transported from the ER to the melanosomes via the Golgi apparatus. In the present study, we demonstrate that Box B-binding factor 2 human homolog on chromosome 7 (BBF2H7), an ER-resident transmembrane transcription factor that functions as an ER stress sensor, is activated by mild ER stress caused by abundant Tyrosinase synthesis. Activated BBF2H7 enhances COPII-mediated anterograde transport by inducing the expression of Sec23a, which is a COPII component and transcriptional target of BBF2H7. Loss of BBF2H7 attenuates the transport of Tyrosinase, leading to its accumulation in the ER lumen and reduced melanin production. Restoration of BBF2H7 or Sec23a expression in Bbf2h7-deficient melanocytes rescues anterograde transport of Tyrosinase from the ER and melanin pigmentation. Collectively, these findings reveal that the BBF2H7-Sec23a axis is essential for the ER-to-melanosome transport of Tyrosinase and subsequent melanin synthesis. Thus, it may be a prospective therapeutic target for disorders related to melanin pigmentation. Full article

Previous studies have identified oxidative stress and inflammatory responses in granulosa cells (GCs) of periparturient dairy cows. However, whether non-esterified fatty acids (NEFA)-induced endoplasmic reticulum (ER) stress is involved in GC apoptosis remains unclear. In this study, treatment with NEFA (0.9 mM, 24 h) activated the ER stress pathway. This was evidenced by increased expression of both CHOP and GRP78. Furthermore, upregulation of pro-apoptotic factors BAX and Caspase-3 and downregulation of the anti-apoptotic factor Bcl-2 were observed. Pretreatment of GCs with 4-phenylbutyric acid (4-PBA, 2.5 mM, 2 h) reversed the ER stress and apoptotic effects. This suggests that NEFA-induced apoptosis is mediated through activation of the PERK pathway of ER stress, and that 4-PBA alleviates this effect. Furthermore, targeted metabolomics revealed disruptions in lipid and hormone metabolism in GCs following NEFA treatment. Analysis revealed an increase in the levels of 26 types of fatty acids, while a decrease was detected in the levels of 3 types of fatty acids. In summary, NEFA induces ER stress and disrupts intracellular fatty acid, ultimately leading to cell apoptosis. Our findings offer valuable insights for developing strategies to regulate follicular development in dairy cows and mitigate the impacts of postpartum negative energy balance (NEB). Full article

Background: Previous studies have indicated an association between endoplasmic reticulum stress (ERS) and the formation of kidney stones. To further investigate this mechanism, this research sought to identify key genes linked to ERS in calcium oxalate (CaOx) kidney stones. Methods: Key cells with the highest ERS-related gene (ERSRG) scores were identified through single-cell analysis. These key cells were then categorized into high- and low-score groups based on their average ERSRG scores. To identify key genes, we analyzed the intersection of key ERSRGs and differentially expressed genes (DEGs) within key cells, focusing on genes demonstrating significant expression differences between control and CaOx kidney stone samples. A nomogram was constructed using these key genes to predict the risk of CaOx kidney stones. Gene set enrichment analysis (GSEA) was further performed to explore the functions of these key genes in the disease. Additionally, secondary clustering analysis was conducted on key cells to identify subtypes and evaluate the expression of key genes within these subtypes. Finally, the identified key genes were validated using quantitative real-time PCR (qRT-PCR) and Western blot analysis on cultured HK-2 cells, which were exposed with 2 mM CaOx for 24 h at 37 °C with 5% CO₂ or incubated with regular culture medium. Results: Endothelial cells were identified as key cells, and nine key genes were pinpointed in CaOx kidney stones: ACSL4, PTK2, DUSP4, MMP7, PHLDB2, TGM2, PPT1, SPARCL1, and LTF. The nomogram developed from these key genes demonstrated robust predictive ability for CaOx kidney stones risk. Additionally, GSEA revealed that olfactory transduction was enriched by key genes except PTK2. Secondary clustering analysis identified four key cell subtypes within endothelial cells, with LTF, MMP7, and SPARCL1 showing significantly differential expression between control and CaOx kidney stones groups across all key cell subtypes. qRT-PCR and Western blot analyses revealed that, compared to the control group, CaOx-exposed HK-2 cells exhibited significantly increased expression of ACSL4, MMP7, TGM2, PPT1, and LTF (p < 0.05), while showing significantly decreased expression of PTK2, DUSP4, SPARCL1, and PHLDB2 (p < 0.05). Conclusions: This study identified key genes associated with ERS in CaOx kidney stones through single-cell and transcriptomic analysis. The discovery of these genes provides new insights into the treatment of CaOx kidney stones and offers valuable references for subsequent research. Future research should focus on elucidating the precise roles of these candidate genes in CaOx stone pathogenesis to assess their potential for therapeutic intervention. Full article

Phthalates are a widely used class of plasticizers known to cause various health issues. Although numerous review articles have addressed the multi-organ toxicities of Phthalates and their metabolites, a specialized review focusing on their nephrotoxicity remains scarce. In this study, the nephrotoxicity of Phthalates and their metabolites is summarized from the views of epidemiological and toxicological evidence. Epidemiological studies have demonstrated a correlation between Phthalate exposure and abnormal urinary albumin-to-creatinine ratio (ACR) as well as glomerular filtration rate (eGFR) in children. In contrast, for adults, the epidemiological evidence for the association between Phthalates and ACR/eGFR remains controversial, necessitating further investigation. In this review, we explore the potential mechanisms by which Phthalates and their metabolites may induce nephrotoxicity. These mechanisms include the following: (1) induction of oxidative stress in renal cells; (2) reduction in aldosterone levels; (3) dysregulation of the renin-angiotensin system; (4) activation of endoplasmic reticulum (ER) stress; (5) renal fibrosis; (6) disruption of sodium and water homeostasis; and (7) activation of the heat shock response defense system. Finally, based on the current understanding, we propose future research directions and necessary efforts to advance knowledge in this field. Full article

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of both diseases through multiple pathways: In pancreatic β-cells, endoplasmic reticulum (ER) calcium imbalance triggers ER stress, mitochondrial dysfunction, and apoptosis, autophagy, and pyroptosis, leading to impaired insulin secretion. Concurrently, calcium overload exacerbates insulin resistance by disrupting insulin signal transduction in peripheral tissues, while hyperinsulinemia further inhibits uric acid excretion through activation of the renal URAT1 transporter, creating a vicious cycle. Additionally, calcium homeostasis dysregulation activates the NLRP3 inflammasome and promotes the release of pro-inflammatory cytokines, aggravating chronic low-grade inflammation, which further deteriorates β-cell function and peripheral metabolic disorders, collectively driving the pathological link between type 2 diabetes and gout. Although calcium channel modulators show potential in improving β-cell function and reducing inflammation, their clinical application faces challenges such as tissue-specific effects and a lack of high-quality clinical trials. We propose that intracellular calcium dysregulation serves as a central pathological amplifier in the diabetes–gout nexus. Future research on targeted calcium signaling interventions, guided by this integrative concept, may help overcome the therapeutic challenges in managing type 2 diabetes complicated by gout. Full article

Tempol, a synthetic nitroxide, exhibits dual antioxidant and pro-oxidant activity, requiring millimolar concentrations to induce oxidative stress, which limits its therapeutic use. Glutathione Peroxidase 4 (GPX4) is a critical lipid peroxidase that prevents ferroptosis, and its inhibition has emerged as a strategy to sensitize cancer cells to oxidative stress. To enhance Tempol’s efficacy, we investigated its interaction with ML210, a GPX4 inhibitor, in human colon (HT29) and gastric (CRL-1739) cancer cell lines. We quantified cell viability, oxidative stress markers (H₂O₂, Total Oxidant Status (TOS), and Total Antioxidant Status (TAS)) and endoplasmic reticulum (ER) stress proteins (ATF6, GRP78, and IRE1α) in in vitro assays. Synergy was assessed using Bliss independence analysis. The combination of Tempol (2 mM) and ML210 (0.05 μM) markedly reduced viability in both cell lines. Bliss analysis revealed slight/moderate synergy for cytotoxicity (Δ = +0.15 in HT29; Δ = +0.26 in CRL-1739) and strong synergy for H₂O₂ accumulation (Δ = +1.92–2.23 across replicates). In contrast, TOS showed moderate-to-strong antagonism across both cell lines, and TAS demonstrated slight synergistic or antagonistic effects. ER stress markers exhibited marker and cell line specific synergy: ATF6 showed strong synergy, IRE1α slight synergy in both lines, and GRP78 activation was highly variable, showing strong synergy in CRL-1739 cells but moderate antagonism in HT29 cells. These findings indicate that the cooperative action of Tempol and ML210 is ROS-pool–specific and pathway-selective in the ER. These findings demonstrate that ML210 potentiates Tempol’s pro-oxidant pressure by targeting GPX4, selectively amplifying H₂O₂ accumulation and ER stress engagement without collapsing global redox balance. This study provides mechanistic rationale for redox–proteostasis co-targeting in gastric and colon cancers and establishes a foundation for in vivo validation. Full article

Lysolecithin, characterized by its superior emulsifying and stabilizing properties, facilitates nutrient absorption and is extensively utilized in aquatic feed formulation. Nevertheless, its precise function in shrimp nutrition and physiology remains inadequately understood. This study aimed to evaluate the feasibility and optimal dosage of replacing 2% soybean lecithin with varying levels of soybean lysolecithin (0–2%) in the diet of Litopenaeus vannamei. Growth performance, antioxidant indices, and lipid metabolism were assessed. The results demonstrated that dietary supplementation with 0.1% lysolecithin had the best growth performance, significantly improved lipid retention and apparent crude fat digestibility, while reducing malondialdehyde (MDA) levels in the hepatopancreas and alleviating endoplasmic reticulum (ER) stress. The 0.1% group also exhibited better hepatopancreatic tissue structure and lipid metabolic homeostasis. In contrast, higher inclusion levels (≥1.5%) led to increased lipid accumulation and enhanced activities of lipid metabolic enzymes but were associated with a risk of oxidative stress and less favorable tissue morphology. No significant differences in antioxidant enzyme activities were observed among groups. It is hypothesized that lysolecithin may regulate lipid metabolism and homeostasis via the Ca²⁺/CaMKKβ/AMPK signaling pathway; further studies are required to confirm this mechanism. In conclusion, 0.1% soybean lysolecithin is recommended as the optimal dietary level for L. vannamei, supporting its feasibility as a substitute for 2% soybean lecithin in shrimp feed. Full article

Neutrophils are among the first cells to be recruited to the lungs during Chlamydia pneumoniae infection in mouse models; however, their regulatory functions are not yet fully understood. This study examined the mechanisms and significance of IL-10-producing neutrophils throughout C. pneumoniae pulmonary infection in C57BL/6 mice. Our findings revealed that infection with C. pneumoniae induces IL-10 secretion in bone marrow-derived neutrophils, depending on Toll-like receptor 2 (TLR2) activation. This process involves TLR2-dependent mitochondrial reactive oxygen species (ROS) production, which triggers the endoplasmic reticulum (ER) stress pathway, including IRE1α and subsequent Xbp1 splicing. Inhibition of this pathway or depletion of neutrophils (using the 1A8 monoclonal antibody) significantly reduces IL-10 levels in bronchoalveolar lavage fluid (BALF) in vivo. Conversely, the absence of IL-10-producing neutrophils, whether through depletion or TLR2 deficiency, leads to increased IL-12p70 and IFN-γ-positive NK cells, along with decreased regulatory T cells and M2-like macrophages. This results in a lower bacterial burden in the lungs but causes more severe pulmonary damage and decreased survival rates. These findings highlight that IL-10 produced by neutrophils via the TLR2-mitochondrial ROS–ER stress pathway is essential for modulating pulmonary immune responses and maintaining immune homeostasis during C. pneumoniae infection, thereby preventing excessive inflammation and tissue damage. Full article

Follicular development is recognized as a highly complex biological process regulated by multiple factors. Thyroid hormone (TH) is considered one of the key regulators of female reproduction, and its dysregulation can significantly impair follicular development. Epigallocatechin gallate (EGCG), the main active component of green tea, possesses strong antioxidant properties. Numerous studies have demonstrated that EGCG positively influences reproductive function in both humans and animals. However, whether EGCG directly affects follicular development under conditions of TH dysregulation remains poorly understood. The primary objective of this study was to investigate the impact of hyperthyroidism on ovarian development, examine whether EGCG could mitigate the adverse effects of TH dysregulation, and elucidate the underlying molecular mechanisms. In the T₄-induced hyperthyroidism rat model, ovarian tissues were serially sectioned for Hematoxylin-Eosin (HE) and Masson’s trichrome staining to assess morphological changes, and follicle numbers were quantified at each developmental stage. Granulosa cell (GC) viability, proliferation, and apoptosis induced by T₃ were evaluated using CCK8, EdU, and TUNEL assays, respectively. Antioxidant enzyme activity was measured, and the expression levels of related proteins were analyzed via Western blotting. Results showed that hyperthyroidism altered ovarian structure, significantly increasing the number of atretic follicles. Levels of antioxidant enzymes, including Superoxide Dismutase (SOD), Glutathione Peroxidase (GSH-PX), and Catalase (CAT), were markedly decreased, whereas the lipid peroxidation product malondialdehyde (MDA) was significantly elevated. Furthermore, all ERS-related proteins, phosphorylated Eukaryotic Initiation Factor 2 Alpha (p-eIF2α), Activating Transcription Factor 4 (ATF4), C/EBP homologous protein (CHOP), and Caspase-3, were upregulated, accompanied by decreased glucose-regulated protein 78 (GRP78) expression. Treatment with EGCG alleviated these detrimental effects of hyperthyroidism. At the cellular level, high concentrations of T₃ reduced GC viability and proliferation while increasing apoptosis. Reactive oxygen species levels were elevated, and GRP78 expression was decreased. Notably, all T₃-induced effects were reversed by EGCG treatment. In summary, this study demonstrates that hyperthyroidism induces oxidative stress in GCs, which triggers endoplasmic reticulum stress via the eIF2α/ATF4 pathway and leads to apoptosis. EGCG mitigates apoptosis by enhancing antioxidant capacity, thereby preserving ovarian function. These findings establish EGCG as a protective agent for maintaining ovarian health and fertility. Full article

The pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1) plays a pivotal role in central nervous system development and homeostasis. Comparisons of PAC1 knockout (PAC1^−/−), heterozygous (PAC1^+/−) and wild-type (PAC1^+/+) mice demonstrate that PAC1 deficiency severely impairs pre-weaning survival and results in marked developmental deficits, including reduced postnatal weight and altered locomotor behavior. PAC1^−/− mice exhibited hyperlocomotion, reduced anxiety-like behavior, and transient deficits in motor coordination. Gene expression analyses revealed widespread dysregulation of oligodendrocyte-associated markers, with significant myelin reduction and decreased mature oligodendrocyte density in the corpus callosum. ER stress was evidenced in both white matter and motor cortex, as indicated by altered expression of UPR-related genes and increased phosphorylated (p)IRE1⁺ neurons. Retinal morphology was compromised in PAC1^−/− animals, with reduced overall retinal and ganglion cell layer thickness. Notably, no gross morphological or molecular abnormalities were detected in the spinal cord regarding myelin content or MBP expression; however, synaptic marker expression was selectively reduced in the ventral horn of PAC1-deficient mice. Together, these findings highlight a critical role for PAC1 in oligodendrocyte maturation, retinal development, and synaptogenesis, providing new insights with relevance in multiple sclerosis and other neurodevelopmental and neurodegenerative conditions. Full article

Obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) represent complex systemic disorders marked by chronic inflammation, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. These pathophysiological processes disrupt insulin signaling and β-cell function, leading to impaired glucose homeostasis across multiple organs. Conventional therapies often target isolated pathways, overlooking the intricate molecular crosstalk and organelle-level disturbances driving disease progression. Citrus-derived polyphenols—including hesperidin, naringenin, nobiletin, and tangeretin—have emerged as promising agents capable of orchestrating a multi-targeted “metabolic reprogramming.” These compounds modulate key signaling pathways, including AMPK, PI3K/Akt, NF-κB, and Nrf2, thereby enhancing insulin sensitivity, reducing pro-inflammatory cytokine expression, and restoring redox balance. Furthermore, they improve mitochondrial biogenesis, stabilize membrane potential, and alleviate ER stress by modulating the unfolded protein response (UPR), thus supporting cellular energy homeostasis and protein folding capacity. Evidence from preclinical studies and select clinical trials suggests that citrus polyphenols can significantly improve glycemic control, reduce oxidative and inflammatory markers, and preserve β-cell function. Their pleiotropic actions across molecular and organ-level targets position them as integrative metabolic modulators. This review presents a systems-level synthesis of how citrus polyphenols rewire metabolic signaling networks and organelle resilience, offering a holistic therapeutic strategy to mitigate the root causes of obesity-induced insulin resistance. Full article

The progression of inflammation during sepsis represents a multifaceted biological cascade that requires effective therapeutic interventions to improve survival. In septic neonatal foals, oxidative stress (OS) arises due to a compromised antioxidant defense system. Oxidative stress may disrupt the functionality of redox-sensitive organelles, such as the endoplasmic reticulum (ER). Endoplasmic reticulum stress disorder affects multiple cellular signaling pathways, including redox balance, inflammation, and apoptosis, and contributes to the pathogenesis of sepsis. The study aimed to elucidate whether OS conditions in sepsis influenced gene expression associated with ER stress. Blood samples were collected from 7 healthy and 21 hospitalized neonatal foals and processed for RNA extraction. RNA sequencing was employed to identify ER stress-responsive genes. Novel findings reported here indicate activation of the ER stress pathway in foals with sepsis. Several genes associated with ER stress, such as clusterin (CLU), BCL2-like 1 (BCL2L1), ubiquitin specific peptidase 14 (USP14), bifunctional apoptosis regulator (BFAR), and optic atrophy 1 (OPA1), were upregulated and positively correlated with sepsis scores and negatively correlated with the combined activities of antioxidant enzymes. In contrast, X-box binding protein 1 (XBP1), homocysteine inducible ER protein with ubiquitin-like domain 1 (HERPUD1), leucine-rich repeat kinase 2 (LRRK2), and selenoprotein S (SELENOS) were negatively correlated with sepsis scores and were downregulated in sepsis and positively correlated with the combined activities of antioxidant enzymes. Furthermore, a positive correlation was observed between cAMP responsive element binding protein 3 like 2 (CREB3L2) and BCL2L1, as well as between the expressions of USP14 and YOD1 deubiquitinase (YOD1) in sepsis. Similarly, the expression levels of XBP1 and Herpud1 demonstrated a positive correlation with each other in sepsis. Additionally, the downregulation of genes with protective function against OS, such as XBP1, HERPUD1, and SELENOS, in septic foals also highlights their significance in mitigating OS in sepsis treatment. The study reported here highlights the potential of ER stress as a promising therapeutic target and prognostic marker in septic foals. Full article

Objectives: This study aimed to establish a transgenic mouse model expressing nucleus-localized human α-synuclein (α-syn) to investigate its impact on the central nervous system and behavior and the underlying mechanisms involved. Methods: A nuclear localization sequence (NLS) was added to the end of the human SNCA (hSNCA) gene. Subsequently, an empty vector and a mammalian lentiviral vector of the hSNCA-NLS were constructed. Transgenic mice were generated via microinjection, with genotyping and protein expression confirmed by PCR and western blotting. Only male mice were used in subsequent behavioral and molecular experiments. Immunofluorescence identified the colocalization of human α-syn with the cell nucleus in mouse brain tissues. Behavioral changes in transgenic mice were assessed using open field, rotarod, and O-maze tests. qPCR and Western blotting detected expression levels of genes and proteins related to inflammation, endoplasmic reticulum stress (ERS), and apoptosis. Bulk RNA sequencing was used to screen for differentially expressed genes and signaling pathways. Results: We successfully constructed a transgenic mouse model expressing human α-syn. Human α-syn was widely expressed in the heart, liver, spleen, kidneys, and brain of the mice, with distinct nuclear localization observed. Behavioral assessments demonstrated that, by 2 months of age, the mice exhibited motor dysfunction alongside astrocyte proliferation and neuroinflammation. At 6 months, the elevated expression of ERS-related genes (ATF6, PERK, and IRE1) and activation of the PERK-Beclin1-LC3II pathway indicated progressive ERS. By 9 months, apoptotic events had occurred, accompanied by significant anxiety-like behaviors. Bulk RNA sequencing further identified key differentially expressed genes, including IL-1α, TNF, PERK, BECLIN, GABA, IL-6α, P53, LC3II, NOS, and SPAG, suggesting their involvement in the observed pathological and behavioral phenotypes. Conclusions: The nuclear localization human α-syn transgenic mice were successfully established. These findings demonstrate that nucleus-localized α-syn induces early motor deficits, which are likely mediated by neuroinflammation, whereas later anxiety-like behaviors may result from ERS-induced apoptosis. This model provides a valuable tool for elucidating the role of nuclear α-syn in Parkinson’s disease and supports further mechanistic and therapeutic research. Full article