The pathogenesis of Parkinson's disease is closely related to genetic factors. This article has systematically reviewed the research progress of molecular genetic mechanism on Parkinson's disease by focusing on the role of six high-penetrance pathogenic genes (SNCA, LRRK2, PRKN, PINK1, PARK7, and VPS35) and some risk genes (such as GBA1). These genetic variants eventually converge in three core pathogenic biological pathways, including lysosomal-autophagy pathway disorder, mitochondrial quality control disorder and α-synuclein metabolic abnormality. In-depth understanding of these molecular mechanisms is of great significance for the development of targeted therapy and realization of precision medicine for this disease.
Humans ; Parkinson Disease/metabolism* ; alpha-Synuclein/genetics* ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics* ; Genetic Predisposition to Disease ; Protein Kinases/genetics* ; Animals ; Glucosylceramidase/genetics* ; Ubiquitin-Protein Ligases/genetics*

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Subarachnoid Hemorrhage/complications* ; Inflammasomes/metabolism* ; Rats ; Mice ; Neuroinflammatory Diseases/metabolism* ; WNK Lysine-Deficient Protein Kinase 1/genetics* ; Male ; Humans ; Chlorides/metabolism* ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Brain Injuries/metabolism* ; Microglia/metabolism* ; Protein Serine-Threonine Kinases

Cancer represents a significant disease that profoundly impacts human health and longevity. Projections indicate a 47% increase in the global cancer burden by 2040 compared to 2020, accompanied by a further rise in the associated economic burden. Consequently, there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer. Natural products (NPs) play a crucial role in the identification and development of anticancer therapeutics. This study identified ustusolate E (UE) and its analog 11α-hydroxy-ustusolate E (HUE) from strain Aspergilluscalidoustus TJ403-EL05, and examined their antitumor activities and mechanisms of action. The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS (human gastric cancer cells) and 786-O (human renal clear cell carcinoma cells), induced irreversible DNA damage, blocked the cell cycle at the G₂/M phase, and further induced apoptosis in tumor cells. To the best of the authors' knowledge, this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms. The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.
Humans ; Apoptosis/drug effects* ; TOR Serine-Threonine Kinases/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases/genetics* ; Signal Transduction/drug effects* ; Tumor Suppressor Protein p53/genetics* ; Cell Proliferation/drug effects* ; Antineoplastic Agents/pharmacology* ; Sesquiterpenes/pharmacology* ; Aspergillus/chemistry*

The protein kinase A/protein kinase G/protein kinase C-family (AGC kinase family) of eukaryotes is involved in regulating numerous biological processes. The 3-phosphoinositide- dependent protein kinase 1 (PDK1), is a conserved serine/threonine kinase in eukaryotes. To understand the roles of PDK1 homologous genes in cell death and immunity in tetraploid Nicotiana tabacum, the previuosly generated transgenic CRISPR/Cas9 lines, in which 5-7 alleles of the 4 homologous PDK1 genes (NtPDK1a/1b/1c/1d homologs) simultaneously knocked out, were used in this study. Our results showed that the hypersensitive response (HR) triggered by transient overexpression of active Pto (Pto^Y207D) or soybean GmMEKK1 was significantly delayed, whereas the resistance to Pseudomonas syrangae pv. tomato DC3000 (Pst DC3000) and tobacco mosaic virus (TMV) was significantly elevated in these partial knockout lines. The elevated resistance to Pst DC3000 and TMV was correlated with the elevated activation of NtMPK6, NtMPK3, and NtMPK4. Taken together, our results indicated that NtPDK1s play a positive role in cell death but a positive role in disease resistance, likely through negative regulation of the MAPK signaling cascade.
Nicotiana/virology* ; Disease Resistance/genetics* ; Plant Diseases/immunology* ; Plants, Genetically Modified/genetics* ; Gene Knockout Techniques ; Plant Proteins/genetics* ; CRISPR-Cas Systems ; Protein Serine-Threonine Kinases/genetics* ; 3-Phosphoinositide-Dependent Protein Kinases/genetics* ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Tobacco Mosaic Virus/pathogenicity*

N⁶-methyladenosine (m⁶A) modification plays a critical role in cell cycle regulation, while the mechanism of m⁶A in regulating mitosis remains underexplored. Here, we found that the total m⁶A modification level in cells increased during mitosis by the liquid chromatography-mass spectrometry/mass spectrometry and m⁶A dot blot assays. Silencing methyltransferase-like 3 (METTL3) or METTL14 results in delayed mitosis, abnormal spindle assembly, and chromosome segregation defects by the immunofluorescence. By analyzing transcriptome-wide m⁶A targets in HeLa cells, we identified polo-like kinase 1 (PLK1) as a key gene modified by m⁶A in regulating mitosis. Specifically, through immunoblotting and RNA pulldown, m⁶A modification inhibits PLK1 translation via YTH N⁶-methyladenosine RNA binding protein 1, thus mediating cell cycle homeostasis. Demethylation of PLK1 mRNA leads to significant mitotic abnormalities. These findings highlight the critical role of m⁶A in regulating mitosis and the potential of m⁶A as a therapeutic target in proliferative diseases such as cancer.
Humans ; Polo-Like Kinase 1 ; Cell Cycle Proteins/metabolism* ; Proto-Oncogene Proteins/metabolism* ; Protein Serine-Threonine Kinases/metabolism* ; Mitosis/physiology* ; HeLa Cells ; Adenosine/genetics* ; Methyltransferases/metabolism* ; RNA, Messenger/metabolism* ; RNA-Binding Proteins/metabolism*

Sucrose non-fermenting 1-related protein kinase 1 (SnRK1) is one of the highly conserved Ca²⁺ non-dependent serine/threonine protein kinases, playing a crucial role in regulating the stress responses, growth, and development of plants. SnRK1 is a three-subunit complex, and it is involved in responding to the signaling transduction induced by low-energy/low-sugar conditions. SnRK1 responds biotic and abiotic stress conditions (such as salt, drought, low/high temperatures, and diseases) through phosphorylation of key metabolic enzymes and regulatory proteins, regulation of transcription, and interactions with other proteins. Furthermore, SnRK1 is not only involved in hormone signaling pathways mediated by abscisic acid (ABA), jasmonic acid (JA) and salicylic acid (SA), but also regulates plant autophagy by inhibiting the activity of target of rapamycin (TOR). In this review, we summarized the current results of research on the discovery, structure, and classification of plant SnRK1 and its roles in the stress responses, growth, and development of plants. Furthermore, this article proposes the directions of future research. This review provides good genetic resources and a theoretical basis for the genetic improvement and biological breeding for enhancing the stress tolerance of crops.
Stress, Physiological/physiology* ; Protein Serine-Threonine Kinases/metabolism* ; Plant Development/genetics* ; Signal Transduction ; Gene Expression Regulation, Plant ; Plant Proteins/physiology* ; Plants/metabolism* ; Arabidopsis Proteins/physiology* ; Plant Growth Regulators/metabolism*

Calcineurin B-like protein (CBL)-interacting protein kinases (CIPKs) are a group of Ser/Thr protein kinases, playing a crucial role in the growth, development, and stress responses of plants. CIPKs can undergo autophosphorylation or target the phosphorylation of other signaling factors in responses to biotic and abiotic stresses. In addition, they are involved in the signaling pathways of plant hormones such as abscisic acid (ABA), gibberellic acid (GA), ethylene (ETH), and salicylic acid (SA) to regulate plant growth and development. Furthermore, CIPKs respond to stresses such as salinity, drought, cold, and heavy metals by forming complexes through specific interactions with CBLs. In this study, we summarized the discovery, structures, classification, regulatory mechanisms, and roles of CIPKs in plant responses to stresses and made an outlook on the future research directions. This review is expected to provide genetic resources and theoretical foundations for the genetic improvement and breeding of crops with stress tolerance.
Stress, Physiological/physiology* ; Protein Serine-Threonine Kinases/genetics* ; Signal Transduction/physiology* ; Plant Growth Regulators/metabolism* ; Plant Proteins/genetics* ; Plants/metabolism*

OBJECTIVE: To observe the effects of Huayu Tongluo (transforming stasis and unblocking collaterals) moxibustion on learning-memory ability and hippocampal mammalian sterile 20-like kinase 1 (Mst1)/nuclear factor κB (NF-κB) p65 pathway related to inflammatory response in rats with vascular dementia (VD). METHODS: A total of 60 male Wistar rats of SPF grade were randomly divided into a sham operation group (12 rats) and a modeling group (48 rats). VD model was established by the method of modified bilateral common carotid artery permanent ligation in the modeling group. Thirty-six rats with successful modeling were randomly divided into a model group, a moxibustion group and a western medication group, with 12 rats in each group. Huayu Tongluo moxibustion was applied at "Dazhui" (GV14), "Baihui" (GV20) and "Shenting" (GV24) in the moxibustion group, 20 min each time, once a day, 7 day-intervention was as one course, and 1 day-interval was taken between two courses, for a total of 3 courses. In the western medication group, piracetam was given 0.72 mg/kg by intragastric administration, twice a day, the course of intervention was same as that of the moxibustion group. The learning-memory ability was detected by Morris water maze test; the morphology of hippocampal CA1 region was observed by HE staining; the mRNA expression of Mst1, M1 microglia markers CD86, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected by real-time PCR; the levels of IL-6 and TNF-α in hippocampus were detected by ELISA; and the protein expression of Mst1 and NF-κB p65 in hippocampus was detected by Western blot in rats of each group. RESULTS: Compared with the sham operation group, the escape latency was prolonged in the model group (P<0.05); compared with the model group, the escape latency was shortened in the moxibustion group and the western medication group (P<0.05). The cells in the CA1 region of hippocampus were disordered, cell collapse and irregular nuclei could be observed in the model group; compared with the model group, the cell arrangement in the CA1 region of hippocampus was more regular, and the damage was improved in the moxibustion group and the western medication group. Compared with the sham operation group, the mRNA expression of Mst1, CD86, IL-6 and TNF-α, as well as the protein expression of Mst1, NF-κB p65 in hippocampus were increased in the model group (P<0.05). Compared with the model group, the mRNA expression of Mst1, CD86, IL-6 and TNF-α, as well as the protein expression of Mst1, NF-κB p65 in hippocampus were decreased in the moxibustion group and the western medication group (P<0.05). Compared with the sham operation group, the levels of IL-6 and TNF-α in hippocampus were increased in the model group (P<0.05). Compared with the model group, the levels of IL-6 and TNF-α in hippocampus were decreased in the moxibustion group and the western medication group (P<0.05). CONCLUSION Huayu Tongluo moxibustion can improve the learning-memory ability of VD rats, the mechanism may be related to regulating the activation of microglia through Mst1/NF-κB p65 pathway, reducing the release of pro-inflammatory factors i.e. IL-6 and TNF-α, so as to alleviating the damage of inflammatory factors in the hippocampus of VD rats.
Animals ; Male ; Rats ; Moxibustion ; Hippocampus/metabolism* ; Rats, Wistar ; Dementia, Vascular/genetics* ; Memory/drug effects* ; Humans ; Transcription Factor RelA/genetics* ; Learning ; Protein Serine-Threonine Kinases/genetics* ; Acupuncture Points ; Interleukin-6/genetics* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal

This study explores the mechanism of Guben Jiannao Liquid on Alzheimer's disease(AD) by regulating autophagy based on the liver kinase B1(LKB1)/adenosine monophosphate-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR) pathway. Male SD rats were randomly divided into the blank group, model group, low-dose and high-dose groups of Guben Jiannao Liquid, and rapamycin group, with 10 rats in each group. Except for the blank group, all other groups of rats were injected bilaterally in the hippocampus with β-amyloid(Aβ)_(1-42) to establish the AD model. The low-dose(6.21 g·kg~(-1)) and high-dose(12.42 g·kg~(-1)) groups of Guben Jiannao Liquid and rapamycin group(1 mg·kg~(-1)) were given the corresponding drugs by gavage, and the blank and model groups were given an equal volume of saline by gavage for four weeks. Morris water maze was used to test the learning and memory ability of rats in each group; hematoxylin-eosin(HE) and Nissl staining were used to observe the morphological and quantitative changes of neurons and Nissl bodies in the CA1 region of rat hippocampus; immunohistochemistry was utilized to detect Aβ-positive cell expression in the CA1 region of rat hippocampus; transmission electron microscopy was employed to observe ultrastructural changes in rat hippocampal tissue, and Western blot was used to examine the protein expression levels of LKB1, p-AMPK/AMPK, p-mTOR/mTOR, Beclin1, p62, and LC3-Ⅱ in the hippocampal tissue of the rats. The results showed that compared with those in the blank group, rats in the model group had elevated evasion latency and decreased number of platform transversal and residence time in the platform quadrant. The number of neurons in the hippocampal area was reduced, and the morphology was impaired. The average integral optical density value of Aβ-positive cells was elevated; the expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were decreased, and the expression levels of p-mTOR/mTOR and p62 were increased. Compared with those in the model group, rats in the low-dose and high-dose groups of Guben Jiannao Liquid had shorter evasion latency, higher number of platform transversal, longer residence time in the platform quadrant, increased number of neurons, decreased expression of Aβ-positive cells and average integral optical density values, and increased number of autophagic lysosomes in hippocampal tissue. The expression levels of LKB1, Beclin1, and LC3-Ⅱ were elevated in the hippocampus of rats in the low-dose group of Guben Jiannao Liquid. The expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were elevated in the hippocampal tissue of rats in the high-dose group of Guben Jiannao Liquid, and the expression levels of p-mTOR/mTOR and p62 were decreased. The findings suggest that Guben Jiannao Liquid can improve cognitive impairment in AD rats, and its mechanism of action may be related to the activation of the LKB1/AMPK/mTOR signaling pathway and the up-regulation of autophagy level.
Animals ; Alzheimer Disease/physiopathology* ; Male ; TOR Serine-Threonine Kinases/genetics* ; Autophagy/drug effects* ; Rats, Sprague-Dawley ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinases/genetics* ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; AMP-Activated Protein Kinase Kinases ; Humans ; Hippocampus/metabolism*