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TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90-95%) are sporadic (sALS), among familial ALS cases 5-10% involve the inheritance of mutations in the gene and the remaining (90-95%) are due to mutations in other genes such as: , and etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like aggregation, its physiological vs. pathological oligomerization , liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.

Autism spectrum disorder is a complex neurodevelopmental disorder that appears during the first three years of infancy and lasts throughout a person's life. Recently a large category of genomic structural variants, denoted as copy number variants (CNVs), were established to be a major contributor of the pathophysiology of autism. To date almost all studies have focussed only on the genes present in the CNV loci, but the impact of non-coding regulatory microRNAs (miRNAs) present in these regions remain largely unexplored. Hence we attempted to elucidate the biological and functional significance of miRNAs present in autism-associated CNV loci and their target genes by using a series of computational tools. We demonstrate that nearly 11% of the CNV loci harbor miRNAs and a few of these miRNAs were previously reported to be associated with autism. A systematic analysis of the CNV-miRNAs based on their interactions with the target genes enabled the identification of top 10 miRNAs namely hsa-miR-590-3p, hsa-miR-944, hsa-miR-570, hsa-miR-34a, hsa-miR-124, hsa-miR-548f, hsa-miR-429, hsa-miR-200b, hsa-miR-195 and hsa-miR-497 as hub molecules. Further, the CNV-miRNAs formed a regulatory loop with transcription factors and their downstream target genes, and annotation of these target genes indicated their functional involvement in neurodevelopment and synapse. Moreover, miRNAs present in deleted and duplicated CNV loci may explain the difference in dosage of the crucial genes controlled by them. These CNV-miRNAs can also impair the global processing and biogenesis of all miRNAs by targeting key molecules in the miRNA pathway. To our knowledge, this is the first report to highlight the significance of CNV-microRNAs and their target genes to contribute towards the genetic heterogeneity and phenotypic variability of autism.

The classical amyloid cascade model for Alzheimer’s disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2 , as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA , could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

Background Skull base meningiomas are chronic conditions that can present with a wide variety of symptoms ranging from near normalcy to chronic and prolonged disability and also often worsen by treatment-related sequelae. Hence, it is necessary to investigate the quality of life (QOL) among patients with skull base meningioma and evaluate the impact of microsurgery on their overall well-being. Methods In this prospective observational study, 36 patients undergoing microsurgery for skull base meningioma were assessed for QOL using SF-36 questionnaires. Results were compared to the QOL of 36 patients with a non-neurosurgical chronic disease (diabetes mellitus) and 36 matched healthy volunteers. This study commenced from 2019 and ended in 2022. Results All QOL parameters in skull base meningioma patients were preoperatively significantly worse than in the healthy population. The most affected QOL domain were role limitation due to physical health (RLPH) and role limitation due to emotional problems (RLEP). Within one year after surgery, skull base meningioma patients showed a significant improvement of all QOL parameters. The domains of physical functioning (PF), emotional well-being (EWB), body pain (BP) and general health (GH) improved to similar values as their matched healthy controls. However, social functioning (SF), RLPH, and RLPE remained still significantly affected. Compared to chronic diabetic patients, the domains PF, EWB, BP, and GH showed significantly better QOL values after one year in skull base meningioma patients, but RLEP and RLPH were worse. Conclusion Microsurgery can significantly improve all QOL domains in skull base meningioma patients within one year. Physical activity, overall health, and mental well-being have been observed to return to even normal levels. While certain QOL domains may still be affected post-microsurgery, it is evident that microsurgery can yield a substantial improvement, ultimately raising QOL to levels surpassing those seen in other non-neurosurgical chronic diseases, such as diabetes mellitus.

Malignant transformation of vestibular schwannoma (VS) post-radiosurgery is an extremely rare but life-threatening complication. We present a patient who underwent two surgeries for a benign VS and received Gamma Knife radiosurgery for residual tumour. Five and a half years post-radiosurgery, the patient was reoperated for symptomatic recurrence of the tumour. Histopathology confirmed the diagnosis of a high-grade spindle cell sarcoma. Although near-total resection was uneventful, the patient deteriorated rapidly, and comfort care was chosen. This report is the 13th documented case of histopathologically confirmed malignant transformation of a benign VS that strictly meets the modified Cahan’s criteria, suggesting the direct link to radiosurgery-induced malignancy.

Background Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. Main text Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. Conclusions Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.

Background Stereotactic radiosurgery effectively controls vestibular schwannoma (VS). However, in certain cases, microsurgical resection may be necessary for post-radiosurgery tumour progression. The characteristics and microsurgical challenges of uncommon cystic recurrences post-radiosurgery are rarely addressed. Method We retrospectively analysed 24 consecutive patients who underwent microsurgical intervention for recurrent VS post-radiosurgery by the senior author. Results Tumour recurrence post-radiosurgery occurred as solid growth in 19 patients (79%), while 5 patients (21%) developed large brainstem-compressing cysts. The median time interval for tumour recurrence post-radiosurgery was similar between cystic and non-cystic recurrent VS (30 vs. 25 months; p =0.08). Cystic recurrences occurred in primarily cystic VS in 3 patients, and new cysts developed in 2 patients with primarily solid VS. Intra-operatively, tumours were firm in 18 cases (75%) and strongly adhered to surrounding structures in 14 cases (58%). All cystic cases underwent cyst decompression, while complete resection of solid tumour components was avoided due to neurovascular adherence. At a mean follow-up of 42±39 months, 12 patients (50%) showed contrast-enhancing tumour residuals in follow-up imaging, including all cystic recurrent cases. Tumour residuals remained stable without requiring further intervention, except for one patient revealing malignant tumour transformation. House-Brackmann grade I/II was preserved in 15 patients (62%). Three patients (13%) developed new facial palsy, and two patients (8%) improved to House-Brackmann grade II. Cystic recurrences had a significantly higher frequency of tumour residuals compared to solid recurrences (100% vs. 37%; p =0.01) but similar rates of facial palsy (60% vs. 32%; p =0.24) Conclusions Cyst development in VS post-radiosurgery is more common in primary cystic lesions but can also occur in rare cases of primary solid VS. Symptomatic cysts require microsurgical decompression. However, complete resection of the solid tumour component is not crucial for long-term tumour control and should be avoided if it risks neurological function in this delicate area.

Severe socioeconomic deprivation (SED) and adverse childhood experiences (ACE) are significantly associated with the development in adulthood of (i) enhanced inflammatory status and/or hypothalamic–pituitary–adrenal (HPA) axis dysfunction and (ii) neurological, neuroprogressive, inflammatory and autoimmune diseases. The mechanisms by which these associations take place are detailed. The two sets of consequences are themselves strongly associated, with the first set likely contributing to the second. Mechanisms enabling bidirectional communication between the immune system and the brain are described, including complex signalling pathways facilitated by factors at the level of immune cells. Also detailed are mechanisms underpinning the association between SED, ACE and the genesis of peripheral inflammation, including epigenetic changes to immune system-related gene expression. The duration and magnitude of inflammatory responses can be influenced by genetic factors, including single nucleotide polymorphisms, and by epigenetic factors, whereby pro-inflammatory cytokines, reactive oxygen species, reactive nitrogen species and nuclear factor-κB affect gene DNA methylation and histone acetylation and also induce several microRNAs including miR-155, miR-181b-1 and miR-146a. Adult HPA axis activity is regulated by (i) genetic factors, such as glucocorticoid receptor polymorphisms; (ii) epigenetic factors affecting glucocorticoid receptor function or expression, including the methylation status of alternative promoter regions of NR3C1 and the methylation of FKBP5 and HSD11β2 ; (iii) chronic inflammation and chronic nitrosative and oxidative stress. Finally, it is shown how severe psychological stress adversely affects mitochondrial structure and functioning and is associated with changes in brain mitochondrial DNA copy number and transcription; mitochondria can act as couriers of childhood stress into adulthood.

Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na + , K + -ATPase, K ir 4.1, aquaporin-4, Cx34 and K ATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted.