SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3.

Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 is an enzyme accounting for removing acetylated lysine residues from target proteins by consuming NAD+, but its role remains elusive in ferroptosis and activating ATF3. In this study, we found SIRT1 was activated during the process of RSL3-induced glioma cell ferroptosis. Moreover, the glioma cell death was aggravated by SIRT1 activator SRT2183, but suppressed by SIRT inhibitor EX527 or when SIRT1 was silenced with siRNA. These indicated SIRT1 sensitized glioma cells to ferroptosis. Furthermore, we found SIRT1 promoted RSL3-induced expressional upregulation and nuclear translocation of ATF3. Silence of ATF3 with siRNA attenuated RSL3-induced increases of ferrous iron and lipid peroxidation, downregulation of SLC7A11 and GPX4 and depletion of cysteine and GSH. Thus, SIRT1 promoted glioma cell ferroptosis by inducting ATF3 activation. Mechanistically, ATF3 activation was reinforced when RSL3-induced decline of NAD+ was aggravated by FK866 that could inhibit NAD + synthesis via salvage pathway, but suppressed when intracellular NAD+ was maintained at higher level by supplement of exogenous NAD+. Notably, the NAD + decline caused by RSL3 was enhanced when SIRT1 was further activated by SRT2183, but attenuated when SIRT1 activation was inhibited by EX527. These indicated SIRT1 promoted ATF3 activation via consumption of NAD+. Finally, we found RSL3 activated SIRT1 by inducing reactive oxygen species-dependent upregulation of AROS. Together, our study revealed SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via activation of ATF3-dependent inhibition of SLC7A11 and GPX4.

Central nervous system clear cell meningioma: a systematic literature review.

Clear cell meningiomas are a rare histological subtype of World Health Organization (WHO) grade II meningioma. Despite its relatively low frequency, clear cell meningioma has attracted considerable attention because of its unique pathological characteristics, clinical behavior, and challenging management considerations. The purpose of our systematic review is to provide clinicians with a better understanding of this rare disease. PubMed was searched for articles in the English language published from 1988 to 2023 June. The keywords were as follows: "clear cell meningioma," "clear cell" and "meningioma." We analyzed clinical manifestations, radiological manifestations, pathological features, comprehensive treatment strategies, and prognosis to determine the factors influencing recurrence-free survival (RFS). Recurrence-free survival curves of related factors were calculated by the Kaplan‒Meier method. The log-rank test and Cox univariate analysis were adopted to assess the intergroup differences and seek significant factors influencing prognosis and recurrence. Fifty-seven papers met the eligibility criteria, including 207 cases of clear cell meningioma (CCM), which were confirmed by postoperative pathology. The fifty-seven articles involved 84 (40.6%) males and 123 (59.4%) females. The average age at diagnosis was 27.9 years (range, 14 months to 84 years). Among the symptoms observed, headache, neurologic deficit, and hearing loss were the most commonly reported clinical manifestations. Most tumors (47.8%) were located in the skull base region. Most tumors showed significant enhancement, and homogeneous enhancement was more common. A total of 152 (74.1%) patients underwent gross total resection (GTR), and 53 (25.9%) patients underwent subtotal resection (STR). During the follow-up, the tumor recurred in 80 (39.4%) patients. The log-rank test and the Cox univariate analysis revealed that tumor resection range (GTR vs. STR) and adjuvant treatment (YES vs. NO) were significant predictors of recurrence-free survival (RFS). Clear cell meningioma is a rare type of meningioma with challenging diagnosis and therapy. The prognosis of this disease is different from that of regular meningiomas. Recurrence remains a possibility even after total tumor resection. We found that the surgical resection range and adjuvant treatment affected the recurrence period. This finding provides significant guidance for the treatment of clear cell meningioma.

Enterovirus D68 Infection Induces TDP-43 Cleavage, Aggregation, and Neurotoxicity.

Enterovirus D68 (EV-D68), which causes severe respiratory diseases and irreversible central nervous system damage, has become a serious public health problem worldwide. However, the mechanisms by which EV-D68 exerts neurotoxicity remain unclear. Thus, we aimed to analyze the effects of EV-D68 infection on the cleavage, subcellular translocation, and pathogenic aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in respiratory or neural cells. The results showed that EV-D68-encoded proteases 2A and 3C induced TDP-43 translocation and cleavage, respectively. Specifically, 3C cleaved residue 327Q of TDP-43. The 3C-mediated cleaved TDP-43 fragments had substantially decreased protein solubility compared with the wild-type TDP-43. Hence, 3C activity promoted TDP-43 aggregation, which exerted cytotoxicity to diverse human cells, including glioblastoma T98G cells. The effects of commercially available antiviral drugs on 3C-mediated TDP-43 cleavage were screened, and the results revealed lopinavir as a potent inhibitor of EV-D68 3C protease. Overall, these results suggested TDP-43 as a conserved host target of EV-D68 3C. This study is the first to provide evidence on the involvement of TDP-43 dysregulation in EV-D68 pathogenesis. IMPORTANCE Over the past decade, the incidence of enterovirus D68 (EV-D68) infection has increased worldwide. EV-D68 infection can cause different respiratory symptoms and severe neurological complications, including acute flaccid myelitis. Thus, elucidating the mechanisms underlying EV-D68 toxicity is important to develop novel methods to prevent EV-D68 infection-associated diseases. This study shows that EV-D68 infection triggers the translocalization, cleavage, and aggregation of TDP-43, an intracellular protein closely related to degenerative neurological disorders. The viral protease 3C decreased TDP-43 solubility, thereby exerting cytotoxicity to host cells, including human glioblastoma cells. Thus, counteracting 3C activity is an effective strategy to relieve EV-D68-triggered cell death. Cytoplasmic aggregation of TDP-43 is a hallmark of degenerative diseases, contributing to neural cell damage and central nervous system (CNS) disorders. The findings of this study on EV-D68-induced TDP-43 formation extend our understanding of virus-mediated cytotoxicity and the potential risks of TDP-43 dysfunction-related cognitive impairment and neurological symptoms in infected patients.

Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression.

Menin (MEN1) is a critical modulator of tissue development and maintenance. As such, MEN1 mutations are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin is abundantly expressed in the nervous system, little is known with regard to its function in the adult brain. Here, we demonstrate that neuron-specific deletion of Men1 (CcKO) affects dendritic branching and spine formation, resulting in defects in synaptic function, learning, and memory. Furthermore, we find that menin binds to the p35 promoter region to facilitate p35 transcription. As a primary Cdk5 activator, p35 is expressed mainly in neurons and is critical for brain development and synaptic plasticity. Restoration of p35 expression in the hippocampus and cortex of Men1 CcKO mice rescues synaptic and cognitive deficits associated with Men1 deletion. These results reveal a critical role for menin in synaptic and cognitive function by modulating the p35-Cdk5 pathway.