ASN NEURO最新文献

We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. The enhanced Atg9 phosphorylation in the absence of dAux promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phosphomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. In relation to pathophysiology, Atg9 phosphorylation at T62 and T69 contributes to dopaminergic neurodegeneration and locomotor dysfunction in a Drosophila PD model. Notably, increased expression of the master autophagy regulator Atg1 promotes dAux-Atg9 interaction. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.

Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.

Magnetic Resonance Imaging (MRI) is commonly used to follow the progression of neurodegenerative conditions, including multiple sclerosis (MS). MRI is limited by a lack of correlation between imaging results and clinical presentations, referred to as the clinico-radiological paradox. Animal models are commonly used to mimic the progression of human neurodegeneration and as a tool to help resolve the paradox. Most studies focus on later stages of white matter (WM) damage whereas few focus on early stages when oligodendrocyte apoptosis has just begun. The current project focused on these time points, namely weeks 2 and 3 of cuprizone (CPZ) administration, a toxin which induces pathophysiology similar to MS. In vivo T₂-weighted (T₂W) and Magnetization Transfer Ratio (MTR) maps and ex vivo Diffusion Tensor Imaging (DTI), Magnetization Transfer Imaging (MTI), and relaxometry (T₁ and T₂) values were obtained at 7 T. Significant changes in T₂W signal intensity and non-significant changes in MTR were observed to correspond to early WM damage, whereas significant changes in both corresponded with full demyelination. Some DTI metrics decrease with simultaneous increase in others, indicating acute demyelination. MTI metrics T₂^A, T₂^B, f and R were observed to have contradictory changes across CPZ administration. T₁ relaxation times were observed to have stronger correlations to disease states during later stages of CPZ treatment, whereas T₂ had weak correlations to early WM damage. These results all suggest the need for multiple metrics and further studies at early and late time points of demyelination. Further research is required to continue investigating the interplay between various MR metrics during all weeks of CPZ administration.

Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.

The fifteen canonical paracrine fibroblast growth factors (FGFs) are organized in five subfamilies that interact with four FGF-receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. Many of these FGFs are expressed in CNS regions where oligodendrocyte (OL) progenitors originate, migrate or differentiate. FGF2 (basic FGF) is considered a prototype FGF and the information about the effects of FGF signaling on OL-lineage cells has evolved largely from the study of FGF2. However, other FGFs from four subfamilies ((FGF1 (FGF1,-2), FGF4 (FGF4,-5,-6), FGF8 (FGF8,-17,-18) and FGF9 (FGF9,-16,-20)) that can interact with the isoforms of FGFRs expressed in OL-lineage cells may also play important roles. We previously reported OL-responses to FGF8 family members. Here, we investigate the effects of members of the FGF1,-4, and -9 subfamilies on proliferation and differentiation of OL progenitors (OPCs), and on cell cycle re-entry and down-regulation of myelin proteins by mature OLs. We found that while FGF2 induced all these responses strongly, FGF4,-6,-9 could do so only transiently and in the presence of exogenous HSPGs, and that FGF5,-16,-20 could not do so even in the presence of heparin or at higher concentrations. Furthermore, we noted that structurally similar FGFs within subfamilies did not always show similarities in their biological effects on OL-lineage cells. Taken together, these studies reveal that FGFs differ in the way they regulate the OL-lineage cells, emphasizes the selectivity and importance of HSPGs as FGF co-receptors in OL-lineage cells and suggests that structural similarity among FGF-subfamily members may not always predict their overlapping biological functions.

There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.

During pathogenesis of Alzheimer's disease (AD), mitochondria suffer alterations that lead to low energy production and reactive oxygen species formation. However, the mechanism of impaired mitochondria homeostasis in AD is not fully understood. We hypothesized that abnormal sphingolipid metabolism in mitochondria could be one of the contributing factors to mitochondrial dysfunction. Synaptic and non-synaptic mitochondria were isolated from 5xFAD and wild type (WT) mice at 3 and 7 months using Ficoll gradient ultracentrifugation, and their function was analyzed using Seahorse assay. Additionally, mitochondria were analyzed using mass spectrometry for proteomics and sphingolipidomics analyses. Sphingolipid levels were also determined in synaptic and non-synaptic mitochondria isolated from AD patients and healthy controls. We found that synaptic mitochondria isolated from 3-months old 5xFAD mice manifest diminished oxygen consumption as compared to WT. Consistently, proteomics analysis showed that proteins related to respiratory electron transport and oxidative phosphorylation were altered in 5xFAD mice. When quantifying the main sphingolipids in mitochondria, we found that Cer 18:0, Cer 22:0, and Cer 24:1 were increased already at 3 months in 5xFAD mice. No increase in ceramides was detected in mitochondria isolated from AD patients. However, increased levels of sphingosine were found in both 5xFAD mice and AD patients when compared to respective controls. We report that the regulation of sphingolipids in mitochondria is abnormal at 3 months of age in 5xFAD mice, as indicated by the accumulation of long-chain ceramides, which increases with age. Sphingosine levels are increased in both the mitochondria of 5xFAD mice and AD patients. Our data suggest that the sphingolipid composition is dysregulated in mitochondria early during AD pathogenesis.