The doublecortin (DCX) gene encodes DCX, a microtubule-associated protein that plays a crucial role in brain development. DCX variants can disrupt microtubule binding and stabilization, interfere with intracellular transport, and affect post-translational modifications. A correlation exists between variant types and clinical severity. Animal models and induced pluripotent stem cell (iPSC) models simulating DCX deficiency revealed the dynamic progression of the disease, which has provided a powerful tool for investigating disease mechanisms and screening therapeutic agents. Currently there is no cure for DCX variants, with treatment primarily relying on anti-epileptic drugs and symptom management. Basic research is now offering new avenues for future therapeutic approaches. This article has summarized the potential pathogenic mechanisms and therapeutic strategies for the DCX variants, with an aim to provide insights for clinical treatment.
Humans ; Doublecortin Protein ; Doublecortin Domain Proteins ; Animals ; Neuropeptides/metabolism* ; Microtubule-Associated Proteins/metabolism* ; Mutation

OBJECTIVE: To carry out genetic testing on two fetuses with prenatal ultrasound finding of polydactyly and renal abnormalities to determine the underlying causes. METHODS: Two fetuses with structural abnormalities detected by prenatal ultrasound at Cangzhou People's Hospital in 2021 were selected as the study subjects. Genomic DNA was extracted from the muscle tissue of the abortus and peripheral blood samples from both parents. Whole-exome sequencing (WES) was conducted on the trio to detect the genetic variants. Quantitative PCR was used to validate the exonic deletions. This study has been approved by the Ethics Committee of Cangzhou People's Hospital (Ethics No.K2020-049). RESULTS: Prenatal ultrasound revealed postaxial polydactylies of fingers and toes and slightly enlarged kidneys with increased echogenicity in fetus 1, along with polydactyly of both hands, enlarged kidneys, and enhanced echogenicity of renal parenchyma in fetus 2. Trio-WES analysis revealed that fetus 1 has harbored a pathogenic c.1339G>A variant of the BBS1 gene, along with a heterozygous 426 bp deletion in the 11q13.2 region, which was unreported previously. The deletion has involved exons 10 and 11 of the BBS1 gene. The two variants were inherited from its mother and father, respectively. Fetus 2 was found to harbor a pathogenic c.539G>A variant and a likely pathogenic c.49G>A variant of the BBS10 gene, which were inherited from its mother and father, respectively. The c.49G>A variant has not been documented in databases and the literature. CONCLUSION Two rare fetuses with Bardet-Biedl syndrome have been diagnosed. Above finding has expanded the mutational spectrum of this syndrome and has important implications for genetic counseling for the affected families.
Humans ; Bardet-Biedl Syndrome/diagnostic imaging* ; Female ; Pregnancy ; Fetus/abnormalities* ; Ultrasonography, Prenatal ; Phenotype ; Polydactyly/diagnostic imaging* ; Exome Sequencing ; Adult ; Genetic Testing ; Male ; Prenatal Diagnosis ; Group II Chaperonins/genetics* ; Microtubule-Associated Proteins

OBJECTIVE: To investigate the clinical characteristics and genetic etiology of a child with Cortical dysplasia, complex, with other brain malformations 4 (CDCBM4) and epilepsy due to a TUBG1 gene variant. METHODS: A child diagnosed with CDCBM4 and epilepsy at the Children's Medical Center of the Affiliated Hospital of Guangdong Medical University in May 2024 was selected as the study subject. Clinical data were retrospectively analyzed. Peripheral venous blood samples were collected from the child and her parents for genomic DNA extraction. Trio-based whole-exome sequencing (WES) was performed, and candidate variants were validated by Sanger sequencing. According to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG), candidate variants were classified for pathogenicity. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Guangdong Medical University (Ethics No.: PJ2021-097). RESULTS: The child, a 4-month-old female infant, had no special facial features, normal limb muscle strength, and increased muscle tone of infantile onset, with generalized tonic-clonic seizures as the main manifestation. During seizures, she exhibited head retroflexion, tightly closed eyes, and tonic convulsions of the limbs, occurring approximately 2-3 times per day. Electroencephalogram suggested bilateral anterior predominant medium-to-high amplitude 7-8 Hz mixed rhythm discharges. Head MRI revealed ventricular system dilatation and pachygyria. Trio-WES results indicated that the child has harbored a TUBG1 gene variant of c.776C>T (p.Ser259Leu). Sanger sequencing verification showed that neither of her parents had carried the same variant, confirming it as de novo in origin. According to the ACMG guidelines, the variant was rated as pathogenic (PS2+PS3+PM2_Supporting+PP3). Combining the child's clinical phenotype, the child was diagnosed as CDCBM4 with epilepsy. CONCLUSION Children with CDCBM4 and epilepsy due to TUBG1 gene variants may show pachygyria or agyria and commonly present with intellectual and motor developmental delays and seizure disorders of variable severity. The heterozygous TUBG1 c.776C>T (p.Ser259Leu) variant is likely the genetic etiology underlying this disorder. The results of this study has expanded the mutational spectrum of the TUBG1 gene associated with CDCBM4 and epilepsy.
Humans ; Female ; Epilepsy/genetics* ; Malformations of Cortical Development/genetics* ; Infant ; Phenotype ; Exome Sequencing ; Microtubule-Associated Proteins/genetics*

Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer's disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.
Humans ; Biomarkers/cerebrospinal fluid* ; Nervous System Diseases/diagnosis* ; Brain Injuries/metabolism* ; Phosphopyruvate Hydratase/cerebrospinal fluid* ; Glial Fibrillary Acidic Protein/blood* ; S100 Calcium Binding Protein beta Subunit/blood* ; tau Proteins/cerebrospinal fluid* ; Ubiquitin Thiolesterase/blood* ; Myelin Basic Protein/cerebrospinal fluid* ; Neurofilament Proteins/blood* ; MicroRNAs/blood* ; Brain Injuries, Traumatic/metabolism*

Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.
Humans ; Neurodegenerative Diseases/metabolism* ; alpha-Synuclein/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism* ; Protein Aggregation, Pathological/metabolism* ; DNA-Binding Proteins/metabolism* ; Animals ; Protein Aggregates/physiology*

Hypoxic-ischemic brain damage (HIBD) is one of the main causes of disability in middle-aged and elderly people, as well as high mortality rates and long-term physical impairments in newborns. The pathological manifestations of HIBD include neuronal damage and loss of myelin sheaths. Tau protein is an important microtubule-associated protein in brain, exists in neurons and oligodendrocytes, and regulates various cellular activities such as cell differentiation and maturation, axonal transport, and maintenance of cellular cytoskeleton structure. Phosphorylation is a common chemical modification of Tau. In physiological condition, it maintains normal cell cytoskeleton and biological functions by regulating Tau structure and function. In pathological conditions, it leads to abnormal Tau phosphorylation and influences its structure and functions, resulting in Tauopathies. Studies have shown that brain hypoxia-ischemia could cause abnormal alteration in Tau phosphorylation, then participating in the pathological process of HIBD. Meanwhile, brain hypoxia-ischemia can induce oxidative stress and inflammation, and multiple Tau protein kinases are activated and involved in Tau abnormal phosphorylation. Therefore, exploring specific molecular mechanisms by which HIBD activates Tau protein kinases, and elucidating their relationship with abnormal Tau phosphorylation are crucial for future researches on HIBD related treatments. This review aims to focus on the mechanisms of the role of Tau phosphorylation in HIBD, and the potential relationships between Tau protein kinases and Tau phosphorylation, providing a basis for intervention and treatment of HIBD.
Humans ; tau Proteins/physiology* ; Phosphorylation ; Hypoxia-Ischemia, Brain/physiopathology* ; Animals ; Oxidative Stress

As an important part of the cytoskeleton, microtubules play a crucial role in many cellular processes, such as cell division, intracellular transport, and maintaining cell morphology. The MAP1 family is an important family of microtubule-associated proteins, which includes three members: MAP1A, MAP1B, and MAP1S. These proteins are widely involved in the dynamic regulation of the cytoskeleton and play a key role in the development and function of the central nervous system, especially in the development and function of neurons. This study reviews the research progress of the MAP1 family, mainly focusing on the structure and function of MAP1 family members, and paying particular attention to their roles in neuronal development and regeneration, regulatory mechanisms, and neurodegenerative diseases.
Humans ; Animals ; Microtubule-Associated Proteins/classification* ; Neurons/cytology* ; Neurodegenerative Diseases/physiopathology* ; Microtubules/physiology* ; Cytoskeleton/physiology*

OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy (¹H-MRS) in patients with advanced Alzheimer's disease (AD). METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent ¹⁸F-APN-1607 PET/MR and simultaneously acquired multi-voxel ¹H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the ¹H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau⁺) voxels and Tau-negative (Tau^-) voxels of the AD patients were compared for PET and ¹H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau⁺ voxels were analyzed. RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau⁺ and 428 Tau^- voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (<i>P<i>0.05). Subgroup analyses revealed that Tau⁺ voxels had higher SUVr and lower Cr and Cho/Cr than Tau^- voxels (<i>P<i>0.05). Compared with the control group, Tau⁺ voxels exhibited higher SUVr and lower Cr (<i>P<i>0.05), while Tau^- voxels showed lower NAA (<i>P=i>0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (<i>P>i>0.05). Within Tau⁺ voxels, NAA, Cho, and Cr were negatively correlated with SUVr (<i>P<i>0.001). CONCLUSIONS The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.
Humans ; Alzheimer Disease/diagnostic imaging* ; Aspartic Acid/metabolism* ; tau Proteins/metabolism* ; Creatine/metabolism* ; Brain/metabolism* ; Biomarkers/metabolism* ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism* ; Aged ; Middle Aged

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Patients with severe pneumonia caused by novel coronavirus infection are often complicated with acute respiratory distress syndrome (ARDS), which has a high mortality. ARDS is characterized by diffuse alveolar damage, pulmonary edema, and hypoxemia. Mitochondria are prone to morphological and functional abnormalities under hypoxia and viral infection, which can lead to cell apoptosis and damage, severely impacting the disease progression. Mitochondria maintain homeostasis through fission and fusion. In ARDS, hypoxia leads to the phosphorylation of dynamin-related protein 1 (Drp1), triggering excessive mitochondrial fission and damaging the alveolar epithelial barrier. Animal experiments have shown that inhibiting this process can alleviate lung injury, providing a potential direction for treatment. The pathology of novel coronavirus infection-related ARDS is similar to that of typical ARDS but more severe. Viral infection and hypoxia disrupt the mitochondrial balance, causing fission and autophagy abnormalities, promoting oxidative stress and mitochondrial DNA (mtDNA) release, activating inflammasomes, inducing the expression of hypoxia-inducible factor-1α (HIF-1α), exacerbating viral infection, inflammation, and coagulation reactions, and resulting in multiple organ damage. Mechanical ventilation and glucocorticoids are commonly used in the treatment of novel coronavirus infection-related ARDS. Mechanical ventilation is likely to cause lung and diaphragm injuries and changes in mitochondrial dynamics, while the lung protective ventilation strategy can reduce the adverse effects. Glucocorticoids can regulate mitochondrial function and immune response and improve the patient's condition through multiple pathways. The mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS is caused by hypoxia and viral proteins, leading to lung and multiple organ injuries. To clarify the pathophysiological mechanism of mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS and explore effective strategies for regulating mitochondrial dynamics balance to treat this disease, so as to provide new treatment targets and methods for patients with novel coronavirus infection-related ARDS. The existing treatments have limitations. Future research needs to deeply study the mechanism of mitochondrial dysfunction, develop new therapies and regulatory strategies, and improve the treatment effect.
Humans ; Respiratory Distress Syndrome/etiology* ; COVID-19 ; Mitochondrial Dynamics ; Mitochondria/metabolism* ; DNA, Mitochondrial ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Dynamins ; SARS-CoV-2