Acta Neuropathologica Communications最新文献

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) exhibit predominantly cytoplasmic phosphorylated inclusions of the protein TDP-43 as the major neuropathological lesion. Phosphorylated TDP-43 can modify protein aggregation and promote neuronal dysfunction and neurodegeneration in models of ALS and FTLD-TDP. The phosphatase calcineurin has previously been shown to directly dephosphorylate TDP-43 in vitro and prevent accumulation of phosphorylated TDP-43 in vivo in C. elegans. However, it is unknown whether dysregulation of calcineurin contributes to increased TDP-43 phosphorylation and neurodegeneration in the mammalian brain. Here we show in an inducible mouse model of ALS/FTLD-TDP driven by expression and cytoplasmic mislocalization of human TDP-43 (rNLS8 mice), calcineurin protein decreases dramatically in the brain. This depletion coincides with increased levels of the TDP-43 kinase CDC7 and accumulation of phosphorylated TDP-43, and precedes frank neurodegeneration. Using brain-wide single nucleus RNA sequencing (snRNAseq) in symptomatic rNLS8 mice, we find cell-type selective reduced expression of catalytic and regulatory subunits of calcineurin predominantly in GABAergic and glutamatergic neurons. In mouse primary neuron culture and C. elegans models of ALS/FTLD-TDP, we demonstrate activation or overexpression of calcineurin protects against accumulation of phosphorylated TDP-43, neurotoxicity, and neurodegeneration. Taken together, our data suggests calcineurin dysregulation may be a major contributor to loss of brain resilience mechanisms against phosphorylated TDP-43. Restoring calcineurin activity may present a new target for intervening in TDP-43 proteinopathies, including ALS and FTLD-TDP.

Regional distributions of amyloid-β (Aβ) and tau accumulation have provided important insights into the pathomechanisms of Alzheimer's disease (AD). While such analyses have typically been conducted through histochemical or clinical imaging studies, we previously reported unique regional associations among Aβ species, tau and other proteins by biochemically analyzing multiple postmortem brain regions. Here, using a new cohort and novel ELISAs, we investigated the regional relationships of Aβ species, tau, neuroglial markers, cathepsins and dipeptidyl peptidases (DPP) across AD stages. Despite a relatively small sample size, this study replicated key prior findings, including a strong regional association between Aβ_1-42 and the postsynaptic maker PSD95 particularly in the early stage, distinct regional distributions of Aβ_1-42 and N-terminally truncated Aβ42 (Aβ_t-42), and a significant association between Aβ_t-42 and tau in AD. Moreover, this study observed that Aβ_1-42 was associated with other synaptic proteins, but not neurofilament proteins. Notably, several proteases, particularly cathepsin B, cathepsin D and DPPIV, exhibited strong regional correlations with total Aβ_x-42, Aβ_t-42, Aβ_x-40, and tau accumulations in AD, forming coordinated regional distribution patterns. Such strong regional associations with late-stage Aβ species and tau were not observed for neuroglial markers. At the microscopic level, these proteases displayed abnormal morphologies proximity to Aβ and tau pathologies. Their coordinated regional distributions with Aβ_t-42, Aβ_x-40, and tau may indicate that these proteases cooperatively promote neurodegenerative cascades in AD.

This study explores the cell fate reprogrammability of H3K27M-mutant pediatric high-grade gliomas (pHGG) using neuronal transdifferentiation as a potential targeted therapy. We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures. In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition. This study demonstrates that pHGGs can be phenotypically redirected toward neuronal-like identities through modulating cell fate differentiation programs. These findings advance the concept of 'differentiation therapy' as a promising intervention to reduce phenotypic plasticity and malignancy in pHGG ecosystems. While these are early in vitro findings, the potential ability to steer and control glioma cells toward stable, less malignant fates offers promising translational potential for patient-centered targeted therapies.

Meningiomas are common intracranial tumors with complex behavior that can be difficult to predict. Historically, morphology has been used to predict tumor aggressiveness and risk of recurrence, but this strategy has limitations as a prognostic tool. DNA methylation, transcriptomics, and copy number data are valuable for identifying groups of tumors with distinct biological signatures, thereby predicting recurrence risk. Multiple risk-stratifying classifiers which incorporate methylation data are available, but to date, a clinically validated risk-predicting classifier which exclusively uses methylation data has not been created. Using samples from 217 patients, we developed, validated, and implemented a clinically applicable methylation classifier for prognostic stratification of meningiomas based on k-means clustering of methylation data. Our classifier is 96% accurate, with 91% of samples receiving high confidence scores in the validation cohort (n = 76). This classifier is unique in that it includes de novo identification of risk groups by DNA methylation, confidence score calculation, internal clinical validation, and public model availability. Our newly validated classifier has the potential to aid diagnostic workup, improve recurrence risk prediction, and enhance clinical management of meningiomas.

Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons-cells that normally express only 3R-tau-induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.

Currently there are no therapeutic agents that are effective against both vestibular schwannoma and meningioma, the two most common tumour types affecting patients with the rare tumour predisposition syndrome NF2-related schwannomatosis. This study aimed to characterise the similarities and differences in the tumour immune microenvironments of meningioma and vestibular schwannoma to identify potential therapeutic targets viable for both tumour types. Publicly available bulk Affymetrix expression data for both meningioma (n = 22) and vestibular schwannoma (n = 31) were used to compare gene expression and signalling pathways, and deconvolved to predict the abundance of the immune cell types present. Publicly available single cell RNA sequencing data for both meningioma (n = 6) and vestibular schwannoma (n = 15) was used to further investigate specific T cell and macrophage subtypes for their signalling pathways, gene expression, and drug targets for predicted drug repurposing in both tumour types. Immune cells comprised a larger proportion of the vestibular schwannoma tumour microenvironment compared to meningioma and included a significantly higher abundance of alternatively activated macrophages. However, these alternatively activated macrophages, alongside other immune cell subtypes such as CD8 + T cells and classically activated macrophages, were predicted to be more active in meningioma than vestibular schwannoma. Despite these differences, T cells and tumour associated macrophages of both vestibular schwannoma and meningioma shared drug-target kinases amenable to drug repurposing with Food and Drug Administration (FDA) drugs approved for other conditions. These include bosutinib, sorafenib, mitoxantrone, and nintedanib which are yet to be clinically investigated for vestibular schwannoma or meningioma. Drug repurposing may offer an expedited route to the clinical translation of approved drugs effective for treating both meningioma and vestibular schwannoma to benefit NF2-related schwannomatosis patients.

Embryonal tumors with multilayered rosettes (ETMR) are rare embryonal tumors that usually affect children under two years old. They are characterized histologically by the presence of multilayered rosettes and by the immunohistochemical expression of LIN28A. Their genetic hallmarks include C19MC amplification, which is most common, followed by DICER1 mutation. Each of these alterations correlates with a specific methylation class in the Heidelberg central nervous system tumor classifier and the National Institutes of Health brain tumor classifier. Meanwhile, 2.5 percent of LIN28A-positive embryonal tumors lack the previously mentioned genetic alterations associated with ETMR. Here, we present and discuss a case of this type. A posterior fossa tumor was found in a five-month-old infant. Histologically, the lesion appeared as an embryonal tumor, lacking multilayered rosettes but showing focal positivity for LIN28A. It did not show C19MC amplification or DICER1 mutation, yet it clustered within the ETMR non-C19MC-altered methylation class of the Heidelberg classifier (V12.5) and the ETMR-DICER class of the NIH classifier. Additionally, a YAP1::MAML2 fusion was identified, a finding not yet associated with these methylation classes.