Cellular and Molecular Neurobiology最新文献

The role of Toll-like receptor 2 (TLR2) in the central nervous system (CNS) is critical in several conditions including neurological disorders such as pain, and neurodegenerative disorders such as Parkinson's disease. Therefore, understanding TLR2 function in the CNS is of considerable importance. In this study, we investigated neuronal responses to individual TLR2 ligands. The expression levels of cytokines increased in the culture in the presence of TLR2 ligands. Additionally, increased lactate dehydrogenase (LDH) was noted during lipoteichoic acid (LTA) stimulation. During LTA stimulation, a decrease in the peak amplitude of Ca^2 + oscillations was observed. MnTBAP, which is a reactive oxygen species (ROS) blocker, inhibited the LTA-induced cell death but had no effect on the peak amplitude of the Ca^2 + spike. Conversely, Pam3CSK4 (P3C) stimulation increased the number of Ca^2 + peaks, which was inhibited by a tumor necrosis factor alpha (TNFα) signaling inhibitor. Our study revealed that several TLR2 ligands, each with different specificities, elicited diverse responses in primary cortical cells. In conclusion, TLR1-TLR2 and TLR2-TLR6 signaling reduces the peak amplitude and induces cell death, and TLR1-TLR2 signaling enhances Ca^2 + dynamics via a TNFα pathway.

As a major neonatal brain disorder, hypoxic-ischemic encephalopathy(HIE) presents with elevated risks of long-term disability and neonatal death. Ferroptosis is a distinct mode of regulated cell death marked by excess intracellular iron, oxidative lipid injury, and suppressed GPX4 activity, and has gained attention as a pivotal mechanism in the development of HIE. Signaling pathways such as Nrf2, TLR4/NF-κB, and endoplasmic reticulum stress(ERS) play critical roles.Vitamin D (VD) and its receptor (VDR), beyond their classical roles in calcium-phosphate homeostasis, as neuroprotective modulators of ferroptosis. VD/VDR signaling promotes antioxidant defenses (e.g., via the Nrf2/HO-1 pathway), restores GPX4 activity, regulates iron and lipid metabolism, and mitigates neuroinflammation.These insights provide a rationale for exploring VD/VDR-based interventions as adjunctive strategies to therapeutic hypothermia, which could potentially be explored to improve neurodevelopmental outcomes in affected neonates.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein. Non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, and circular RNAs-have emerged as critical regulators in PD pathogenesis by modulating pathways such as neuroinflammation, mitochondrial function, and protein clearance. Furthermore, exosomal ncRNAs facilitate intercellular communication, propagating pathological signals but also offering therapeutic potential. This review synthesizes the current understanding of ncRNA involvement in PD, structuring the analysis around key pathogenic mechanisms. We provide a critical perspective on the strengths and weaknesses of the current evidence, evaluate the major challenges facing the field-including biomarker validation and therapeutic delivery-and propose a path forward for future research. A deeper, more integrated understanding of these ncRNA networks is essential for developing novel diagnostics and treatments to halt the progression of PD.

Tau is a microtubule-associated protein encoded by the MAPT gene and is mainly expressed in neurons. Alternative splicing generates preferentially six isoforms differing in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R). Isoform expression varies by cell type, developmental stage, and neuronal maturation. Structurally, 4R isoforms bind and stabilize microtubules more effectively than 3R isoforms, while 3R variants are more prone to oligomerization. Differences among isoforms also affect aggregation and post-translational modification patterns, yet their specific roles in tauopathies remain unclear. Beyond its role in microtubule stabilization, tau is increasingly recognized for its functions in other cellular compartments, particularly mitochondria, where it may contribute to mitochondrial dysfunction in neurodegenerative diseases. Its intrinsically disordered conformation and extensive post-translational modifications enable interactions with multiple mitochondrial components, linking tau biology to broader aspects of neuronal health and pathology. The main focus of this review is to analyze how tau protein interacts with mitochondria and disrupts their function. Literature evidence indicates that tau localizes to the outer mitochondrial membrane, intermembrane space, and matrix, where it interferes with key processes. These include disruption of electron transport chain activity, inhibition of ATP synthase, and reduced ATP production, ultimately compromising neuronal energy supply. In parallel, tau destabilizes microtubule-based trafficking, impairing axonal transport and mitochondrial distribution, while also disrupting fission and fusion dynamics that shape mitochondrial morphology. Quality control pathways are affected as well, with tau altering mitophagy and mitochondria-nucleus signaling. Moreover, tau dysregulates calcium buffering and increases reactive oxygen species production, thereby promoting synaptic dysfunction, oxidative stress, and mitochondrial damage. Collectively, these facts establish tau as a central mediator of mitochondrial impairment and neuronal vulnerability. Elucidating the mechanisms by which tau affects mitochondrial physiology underscores its importance as a therapeutic target, with strategies aimed at preserving mitochondrial integrity offering promising avenues to slow neurodegenerative progression. In the last section, we include examples of clinical applications currently in various phases of testing, some of which show promising potential for implementation.

Noise-induced hearing loss (NIHL) is a primary contributor to tinnitus, involving mechanisms such as inflammatory damage, central sensitization, and auditory cortex remodeling. However, not all cases of tinnitus are accompanied by NIHL, and the precise relationship between the two remains incompletely understood. Phosphorylation/dephosphorylation, as a core mechanism for fine cellular regulation, influences neuronal excitability, immune responses, and disease development by modulating protein activity, signal transduction, and gene expression. We hypothesized that aberrant phosphorylation levels may alter auditory cortex neuron function, leading to pathological changes at the protein level. Leveraging auditory cortex tissue from a noise-induced tinnitus model, we systematically investigated the pathogenesis of tinnitus and its distinction from NIHL through integrated proteomic and phosphoproteomic analyses. Compared to animals with NIHL alone, the tinnitus model exhibited enhanced neuronal excitability, synaptic dysfunction, hyperactive energy metabolism, and weakened neuroprotection, with disordered membrane receptor function playing a critical role. Multi-omics analysis further revealed that tinnitus development primarily depends on phosphorylation-mediated post-translational modifications reshaping cellular function, rather than changes in protein abundance caused by alterations in gene transcription levels. Collectively, this study elucidates the physiological and cellular structural alterations in noise-induced tinnitus from the dimensions of protein expression and phosphorylation modification. It confirms that tinnitus leads to neural dysfunction through abnormal membrane receptor activity, and the characteristic proteins and phosphorylation sites identified offer novel therapeutic targets for modulating central hyperexcitability in tinnitus.

Glioblastoma (GB) is among the most aggressive and treatment-resistant brain tumors, largely due to its heterogeneous tumor microenvironment (TME) and the protective nature of the blood-brain barrier (BBB). Recent advances have highlighted the therapeutic potential of neural stem cells (NSCs), which possess tumor-homing capabilities that enable them to selectively migrate toward and infiltrate GB sites. Engineered NSCs can deliver therapeutic agents, including oncolytic viruses, prodrug-converting enzymes, and genetic materials, offering targeted treatment while minimizing systemic toxicity. Preclinical studies have demonstrated NSCs' promise in enhancing drug delivery, modulating the TME, and promoting anti-tumor immune responses. However, translational hurdles persist, including tumor heterogeneity, species-specific immune responses, and challenges in ensuring long-term safety. Emerging strategies-such as genetic modification to improve tumor targeting and the incorporation of biomaterials to enhance retention-are under investigation. Integrating personalized medicine approaches may further optimize NSC-based therapies by tailoring treatment to individual patient profiles. While significant barriers remain, ongoing research may ultimately establish NSCs as a viable and effective platform for GB therapy.

Alzheimer's disease (AD) is a complex neurodegenerative disorder. Recent studies have demonstrated that the dysregulated metabolism of metal ions, particularly copper and iron imbalance in the brains of AD patients,  is closely associated with the pathogenesis of Alzheimer's disease. Based on GEO database and GeneCards database, this study screened and identified 1191 AD-related differentially expressed genes (DEGs), as well as 671 and 682 genes highly associated with copper and iron metabolism. The intersection analysis yielded 26 differentially expressed copper- and iron-related genes (DECIGs). GO and KEGG enrichment analysis indicated that most of them were involved in cellular energy metabolism. PPI network analysis identified 12 hub genes, five of which had AUC values greater than 0.8, indicating strong diagnostic potential. qRT-PCR validation revealed that three hub genes (GOT1, LDHA, and UQCRFS1) showed significant differences in the expression levels between the AD and the control group. The multigene diagnostic model based on the three genes exhibited considerable diagnostic value.

Perineuronal nets (PNNs) are key regulators of neuronal excitability, yet whether they are altered during neurogenic hypertension is unknown. Here, we mapped the developmental trajectory of PNNs in the paraventricular nucleus of the hypothalamus (PVN), a crucial nucleus involved in blood pressure (BP) regulation, and examined their modulation in neurogenic hypertension. We show that PNNs in the PVN follow a developmental pattern similar to other brain regions. The most prevalent neuron subtype enwrapped by PNNs was neuronal nitric oxide synthase (nNOS)-expressing neurons in both sexes, and sex differences were observed only in oxytocin (OXT)-enwrapped neurons. In the DOCA-salt mouse model of neurogenic hypertension, males, but not females, exhibit an increased number and area of PNNs in the PVN with increased excitatory/inhibitory (E/I) ratio. Given that PNNs modulate neuronal activity, our findings may implicate recruitment of previously "silent" neurons as potential contributors of PVN hyperactivity in hypertension. These results demonstrate that PNN remodeling is associated with neurogenic hypertension in male mice.

Stroke is a health problem all over the world. It is a primary cause of disability and ranked number two death cause. In kingdom of Saudi Arabia KSA, the prevalence of stroke in the KSA estimated to be more than 40 per 100 thousand in 2021. The incidence of stroke is increasing in KSA. The risk factors for stroke are grouped into modifiable and nonmodifiable. The modifiable risk factors include diabetes, hyperlipidemia physical inactivity, and diet, whereas the nonmodifiable include sex, age, and race/ethnicity. Decreasing the modifiable risk factors reduces the burden of stroke in population. The long noncoding RNAs (LncRNAs) ANRIL is suggested as a biomarker and treatment target for stroke. The Transcription factor 7-like 2 (TCF7L2) has crucial roles in biological and pathological processes such as inflammation, metabolism, and atherosclerosis. In this study, we examined the associations of ANRIL rs1333045 C>T, CYP2C19*17 (C806T, rs12248560C>T, and TCF7L2 rs12255372 G>T with stroke in 100 stroke cases and 100 matched healthy controls from Tabuk population using the amplification refractory mutation system PCR (ARMS-PCR). Results indicated that the T allele of the ANRIL rs1333048 C>T was associated with stroke with Odd ratio (OR) = 1.73, P value-0.0067. Likewise, the GT genotype and the T allele of the TCF7L2 rs12255372 G>T were associated with stroke with OR = 2.14, P value = 0.01, and 1.9, P value = 0.004, respectively. In addition, the CT genotype and T allele of the CYP2C19*17 (rs12248560) C>T were also associated stroke with OR = 2, P value = 0.02 and OR = 2.3, P value = 0.002, respectively. We conclude that ANRIL rs1333045 C>T, CYP2C19*17 (C806T, rs12248560C>T, and TCF7L2 rs12255372 G>T are potential loci for susceptibility to stroke. This will assist in treatment and/or prevention of cerebrovascular disease.

The SH-SY5Y cell line is a triple-cloned subline of SK-N-SH cells originally isolated in the early 1970s from a bone marrow biopsy of a four-year-old female patient suffering from neuroblastoma. Since then, this cell line has been used as one of the major cell culture models in neuroscience and to study neurodegeneration, as it comprises many of the biochemical and functional properties of neural precursor cells. Differentiation of neuronal precursor cells into a more mature phenotype represents one of the key steps and directed differentiation utilising various reagents is thought to provoke a defined neuronal subtype. Unfortunately, until now there is no consensus, which protocol shall be utilised to reach a specific neuronal subtype. Thus, the aim of the present work was to evaluate four common standard protocols for the differentiation of SH-SY5Y cells and to investigate the respective influences of varying parameters of these differentiation strategies. For this purpose, morphological analyses, mass spectrometry-based quantification of specific marker proteins, time-course protein expression profiling and global proteomics were conducted. On the level of morphology a low serum concentration favoured the abundance of mature neuronal cells containing long and branched neurites. Further low serum levels favoured the expression of dopaminergic marker proteins, in particular DDC, especially when utilising retinoic acid as differentiation agent. Our study clearly shows that an a priori characterisation of SH-SY5Y cells is indispensable to assess the abundance of neuronal subtypes and by that to ensure that the utilised differentiation approach is appropriately aligned with the specific research question.