Acta Neuropathologica Communications最新文献

The vast majority of tumours in the sellar region are pituitary neuroendocrine tumours, also called pituitary adenomas. Sellar gangliocytomas (GCs), benign tumours that originate from neuronal ganglionic cells, account for less than 1% of sellar tumours. Even rarer are mixed gangliocytoma-pituitary neuroendocrine tumours (GC-PitNET). These tumours are often associated with hormone hypersecretion, most commonly resulting in acromegaly. The histogenesis of mixed GC-PitNET is currently unclear. In this paper, we present comprehensive clinical, immunohistochemical, targeting enrichment next generation DNA sequencing, and genome-wide methylation data from four patients with mixed GC-PitNETs, three with acromegaly and one with Cushing's disease. Transcriptomic data are also included for two of the patients. Our findings indicate that mixed GC-PitNETs have different clinical course, with the acromegaly patients showing greater resistance to pharmacological therapy, as well as different protein expression and molecular features compared to respective pure PitNETs. The transcriptomic data on two patients with somatotroph GC-PitNET show involvement of mitochondrial and ribosomal genes, suggesting a distinct gene expression pattern, in comparison with pure somatotroph tumours. Furthermore, the expression pattern of selected stem cell markers, mainly SOX9, supports a common origin of the neuroendocrine and ganglionic tumour components, suggesting the involvement of stem cells in tumorigenesis.

Background: Meningiomas are the most common primary intracranial tumor in adults and systemic therapy is urgently needed for high-grade fatal tumors and those cannot be completely removed by surgery. Multiomics studies have established a molecular classification system in addition to the grading system by the World Health Organization, and SWI/SNF-related BAF chromatin remodeling complex subunit B1 (SMARCB1) mutation was enriched in the immunogenic subgroup. Meningiomas are myeloid-dominant tumors with abundant and unevenly distributed CD163⁺ macrophages, a feature linked to intratumoral heterogeneity. However, the biological drivers of this phenomenon remain unknown.

Methods: A study cohort consisting of 113 patients was established to examine the association between serum immune profile and relapse-free survival. The second study cohort containing 35 patients across different WHO grades and disease states was established to validate and identify immune cell infiltration in the tumor microenvironment. Spatial distribution of immune cells was accessed by immunohistochemistry staining and multiplex immunofluorescence staining. Single-cell RNA sequencing (RNA-seq), bulk RNA-seq and whole exon seq data were analyzed to identify genomic signatures that represent the immunogenic subgroup of meningiomas. Public databases were explored to determine a potential mechanistic link between SMARCB1 and the interleukin-17/colony stimulating factor 1 (IL-17/CSF1) axis.

Results: Serum IL-17 A and IL-5 levels favored a good prognosis of meningioma. CD163⁺ macrophages were enriched in meningiomas regardless of the WHO grade and disease status (primary or recurrent). Compared to CD25⁺/Foxp3⁺ regulatory T cells and CD15⁺/CD33⁺ myeloid-derived suppressor cells, CD163⁺ macrophages tend to be more enriched around SMARCB1-deficient tumor cells. RNA-seq revealed that a 14-gene signature, including IL-17, CSF1, and related upstream and downstream genes, accurately characterizes the immunogenic subtype of meningiomas.

Conclusion: The findings reveal that the infiltration of CD163⁺ macrophages in meningioma may be mediated by the IL-17/CSF1 axis through SMARCB1 regulation.

Lens epithelium-derived growth factor (LEDGF), encoded by the Psip1 gene, exists in two splice variants, LEDGF/p75 and LEDGF/p52. Although little is known about its role in the brain, LEDGF has been proposed to play a role in neurogenesis. Since known LEDGF binding partners, such as PogZ, CDA7L, MLL1 and MeCP2 are implicated in neurological dysfunction, we investigated the role of LEDGF in mouse brain. We developed a conditional Psip1 knock-out (cKO) mouse model by crossbreeding Psip1^fl/fl mice with Nestin^Cre mice, resulting in neuronal depletion of both isoforms in the central nervous system. In wild-type (WT) animals, brain region-dependent alternative splicing was evidenced, with more p75 over p52 in the cerebellum and more p52 over p75 in the hippocampus. Behavioral phenotyping revealed that already at a young age, Psip1 cKO mice show motor deficits. In cerebellar neurons, LEDGF depletion results in more and smaller MeCP2 condensates. Bulk and comparative RNA sequencing of cerebellar extracts revealed downregulation of genes involved in synaptic transmission. Moreover, transcription factor network analysis showed that the differentially expressed genes are mainly regulated by the Polycomb repressive complex 2 (PRC2). Since the LEDGF/p75 binding partner MLL1 is part of the Trithorax Complex, the counterpart of PRC2 in gene regulation, our data highlight the importance of LEDGF/p75-mediated regulation of synaptic gene expression in the cerebellum through Trithorax.

Transgenic mice overexpressing bank vole prion protein with the isoleucine 109 polymorphism, TgVole(I109)4x, develop spontaneous neurodegenerative disease with sex-dependent onset, averaging 170 days in females and 200 days in males at terminal stage. The clinical and pathological features closely resemble Gerstmann-Sträussler-Scheinker syndrome (GSS), with characteristic ataxia, dysmetria, kyphosis, and prominent PrP plaques. Biochemical analysis reveals an atypical prion protein banding pattern with a distinctive low molecular weight band (7-10 kDa) following proteinase K digestion, similar to other atypical prion diseases such as small ruminants atypical scrapie (AS). Importantly, these spontaneously generated prions are highly infectious when passaged to mice expressing the same I109 polymorphism as well as to wild bank voles carrying the I109 polymorphism, but not to models expressing the methionine variant at this position, demonstrating the critical role of this specific polymorphism in atypical prion propagation. Temporal analysis reveals that infectious prions emerge significantly (2-3 months) before clinical signs appear, offering important insights into the pre-clinical phase of prion diseases. Serum neurofilament light chain levels increase significantly at 80 days of age, approximately 100 days before clinical onset, providing a wide therapeutic window with a reliable biomarker. The TgVole(I109)4× model exhibits extraordinary versatility in propagating diverse prion strains, showing remarkable susceptibility to atypical prions (including GSS and AS) with exceptionally short incubation periods, while maintaining the ability to efficiently propagate classical and recombinant prion strains. We present here a thoroughly characterized transgenic mouse model that spontaneously develops an atypical, bona fide prion disease with sex-related differences in disease onset. This model offers valuable insights into spontaneous and atypical prionopathies while demonstrating exceptional versatility for studying diverse prion strains and potential utility for evaluating therapeutic interventions when used with appropriate study designs that account for individual variability.

Schizophrenia (SZ) is epidemiologically linked to an increased risk of developing age-related dementias (ARD) predominantly characterized by Alzheimer's disease and vascular dementia. However, the molecular mechanisms underlying this association remain insufficiently elucidated. Extracellular vesicles (EVs) play a critical role in neuropathological processes and offer a promising avenue for identifying shared disease mechanisms and potential circulating markers for patient stratification. Here we used a two-phase systems biology approach integrating discovery-driven proteomics with a targeted validation strategy using data-independent acquisition mass spectrometry (DIA-MS) in a large, independent SZ cohort. First, we analyzed brain-derived EVs (bEVs) from post-mortem SZ and ARD subjects to identify shared molecular signatures. Next, we validated the presence and circulation of these bEV markers in circulating plasma EVs (pEVs) using DIA-MS data. Remarkably, SZ and ARD bEV proteome and peptidome showed overlapping alterations in neuronal connectivity, synaptic integrity, neuroinflammation, and metabolism. Unsupervised clustering analysis of correlated bEV/pEV markers stratified SZ patients into two clusters: high dementia risk and control-like profiles. Collectively, these data emphasize the significance of bEVs as crucial mediators of shared neuropathogenic mechanisms in SZ, and ARD. Furthermore, we identified a set of pEVs markers, including proteins and specific peptides, with a robust and promising bench-to-bedside trajectory that may facilitate the stratification of SZ patients at risk for ARD.

Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2B^In5 and CHMP2B^Δ10. Here, we found that wildtype CHMP2B (CHMP2B^WT) is mostly present in the cytoplasm, but CHMP2B^In5 is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2B^WT and ALS-associated CHMP2B^Q206H, and its loss in CHMP2B^In5 is responsible for the observed nuclear mislocalization. CHMP2B^Δ10 remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2B^In5 in FTD3 pathogenesis.