Targeting mechanics-induced trabecular meshwork dysfunction through YAP-TGFß Ameliorates high myopia-induced ocular hypertension.

High myopia is a risk factor for primary open angle glaucoma (POAG). The pathological mechanism of high myopia induced POAG occurrence is not fully understood. In this study, we successfully established the guinea pig model of ocular hypertension with high myopia, and demonstrated the susceptibility of high myopia for the occurrence of microbead-induced glaucoma compared with non-myopia group and the effect of YAP/TGF-ß signaling pathway in TM pathogenesis induced by high myopia. Moreover, we performed stretching treatment on primary trabecular meshwork (TM) cells to simulate the mechanical environment of high myopia. It was found that stretching treatment disrupted the cytoskeleton, decreased phagocytic function, enhanced ECM remodeling, and promoted cell apoptosis. The experiments of mechanics-induced human TM cell lines appeared the similar trend. Mechanically, the differential expressed genes of TM cells caused by stretch treatment enriched YAP/TGF-ß signaling pathway. To inhibit YAP/TGF-ß signaling pathway effectively reversed mechanics-induced TM damage. Together, this study enriches mechanistic insights of high myopia induced POAG susceptibility and provides a potential target for the prevention of POAG with high myopia.

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development.

FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and function. Individuals affected by FOXG1 syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of Foxg1 deficiency on myelin development in the mouse brain by conditional deletion of Foxg1 in neural progenitors using NestinCreER;Foxg1fl/fl mice and tamoxifen induction at postnatal day 0 (P0). We found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that Foxg1 deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of Foxg1 in myelin development and provide new clues for further exploring the pathological mechanisms of FOXG1 syndrome.

Diffusional kurtosis imaging in evaluation of microstructural changes of spinal cord in cervical spondylotic myelopathy feasibility study.

To explore the value of diffusion kurtosis imaging in the changes of spinal cord microstructures in patients with early cervical spondylotic myelopathy.Twenty nine patients with cervical myelopathy were selected in this study. All images were acquired on a 3.0 T MR scanner (Skyra, Siemens Medical Systems, Germany). The imaging parameters for diffusion kurtosis imaging were as follows: repetition time/echo time, 3000/91 ms; averages, 2; slice thickness/gap, 3/0.3 mm; number of slices, 17; field of view, 230 × 230 mm; Voxel size, 0.4 × 0.4 × 3.0 mm; 3 b-values (0, 1000, and 2000 s/mm) with diffusion encoding in 20 directions for each b-value. Values for fractional anisotropy, mean diffusivity, and mean diffusional kurtosis (MK) were calculated and compared between unaffected and affected spinal cords.In all patients MK was significantly lower in normal appearing spinal cords adjacent to the affected cervical spinal cords than in normal cervical spinal cords (0.862 ±â€Š0.051 vs 0.976 ±â€Š0.0924, P < .0001), but the difference of fractional anisotropy and apparent diffusion coefficient was no significant (P > .05). The affected cervical spinal cords had lower MK (0.716 ±â€Š0.0753), FA and higher apparent diffusion coefficient than normal cervical spinal cords (P < .001).MK values in the cervical spinal cord may reflect microstructural changes of spinal cord damage in cervical myelopathy, and it could potentially provide more information that obtained with conventional diffusion metrics.

A30P mutant α-synuclein impairs autophagic flux by inactivating JNK signaling to enhance ZKSCAN3 activity in midbrain dopaminergic neurons.

Mutations in α-synuclein gene have been linked to familial early-onset Parkinson's disease (PD) with Lewy body pathology. A30P mutant α-synuclein is believed to suppress autophagic progression associated with PD pathogenesis. However, the mechanistic link between A30P mutation and autophagy inhibition in PD remains poorly understood. In this study, we identified that A30P mutant α-synuclein resulted in reduced autophagy flux through promoting the decrease of autophagosomal membrane-associated protein LC3 and the increase of SQSTM1/p62 protein levels in midbrain dopaminergic neuron, due to the transcriptional repressor ZKSCAN3 trafficking from the cytoplasm to the nucleus. Moreover, the results demonstrated that A30P mutant α-synuclein not only decreased the phospho-c-Jun N-terminal Kinase (p-JNK) levels in midbrain dopaminergic neuron but also interfered autophagy without influencing the activities of AMPK and mTOR. Collectively, the present study reveals a novel autophagy inhibition mechanism induced by A30P mutant α-synuclein via transcriptional activation of the ZKSCAN3 in a JNK-dependent manner.

A novel function for Foxm1 in interkinetic nuclear migration in the developing telencephalon and anxiety-related behavior.

Interkinetic nuclear migration (INM) is a key feature of cortical neurogenesis. INM functions to maximize the output of the neuroepithelium, and more importantly, balance the self-renewal and differentiation of the progenitors. Although INM has been reported to be highly correlated with the cell cycle, little is known about the effects of cell cycle regulators on INM. In this study, by crossing Foxm1(fl/fl) mice with Emx1-Cre line, we report that a conditional disruption of forkhead transcription factor M1 (Foxm1) in dorsal telencephalon results in abnormal cell cycle progression, leading to impaired INM through the downregulation of Cyclin b1 and Cdc25b. The impairment of INM disturbs the synchronization of apical progenitors (APs) and promotes the transition from APs to basal progenitors (BPs) in a cell-autonomous fashion. Moreover, ablation of Foxm1 causes anxiety-related behaviors in adulthood. Thus, this study provides evidence of linkages among the cell cycle regulator Foxm1, INM, and adult behavior.

Bmi-1 absence causes premature brain degeneration.

Bmi-1, a polycomb transcriptional repressor, is implicated in cell cycle regulation and cell senescence. Its absence results in generalized astrogliosis and epilepsy during the postnatal development, but the underlying mechanisms are poorly understood. Here, we demonstrate the occurrence of oxidative stress in the brain of four-week-old Bmi-1 null mice. The mice showed various hallmarks of neurodegeneration including synaptic loss, axonal demyelination, reactive gliosis and brain mitochondrial damage. Moreover, astroglial glutamate transporters and glutamine synthetase decreased in the Bmi-1 null hippocampus, which might contribute to the sporadic epileptic-like seizures in these mice. These results indicate that Bmi-1 is required for maintaining endogenous antioxidant defenses in the brain, and its absence subsequently causes premature brain degeneration.

Hypothesis: multiple factors are associated with the lack of any beneficial effects of oestrogen-replacement therapy in the late postmenopausal stage.

1. Epidemiological and clinical studies suggest that women may obtain cognitive benefits from oestrogen-replacement therapy (ERT) during menopause transition rather than in the post-menopausal stages. However, the underlying mechanisms remain to be determined. 2. We propose that long-term oestrogen deficiency may result in abnormal distribution and localization of brain oestrogen receptors, brain mitochondrial dysfunction, septohippocampal cholinergic degeneration and reactive gliosis. These multiple pathogenic factors may account for the lack of any beneficial effects of ERT in post-menopausal women with or without Alzheimer's disease.