In this article [1], the given and family names of Janna van Wetering were incorrectly structured. The name was displayed correctly in all versions at the time of publication. The original article has been corrected.

Parkinson’s disease (PD) is defined by the progressive loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-syn), yet the molecular determinants of selective neuronal vulnerability remain unresolved. Increasing evidence implicates mitochondria—and particularly their membranes—as critical platforms where α-syn is toxic. This review highlights how α-syn engages mitochondrial membranes through two interconnected processes: classical aggregation and liquid‒liquid phase separation. Both pathways disrupt membrane architecture, compromise respiratory chain function, and impair mitophagy. A pivotal mediator of these events is cardiolipin (CL), a mitochondria-specific phospholipid essential for cristae organization and quality control pathways. Despite extensive progress, the precise mechanistic contributions of CL to α-syn aggregation, phase transitions, and neuronal degeneration remain poorly defined. Clarifying this interplay is crucial, as CL not only binds α-syn with high affinity but also determines whether it remains in a functional state or progresses toward toxic assemblies. By integrating recent advances, we propose a unifying perspective on CL as a molecular switch at the crossroads of mitochondrial biology, protein aggregation, and phase behavior. Beyond mechanistic insight, this view underscores the potential of CL as a target for the development of mitochondria-directed therapies in PD.

In response to the groundbreaking study by Stepankova et al. (Acta Neuropathol Commun 13:89, 2025) demonstrating that activated α9 integrin enables sensory axon regeneration after spinal cord injury, this letter provides a critical perspective on the mechanistic underpinnings and translational implications of their findings. While acknowledging the significance of identifying α9 integrin as a potent pro-regenerative driver, we highlight several areas requiring deeper investigation. Specifically, we interrogate the precise ligand-receptor interactions within the inhibitory injury environment and potential crosstalk with inhibitory signaling pathways. Furthermore, we raise critical concerns regarding the long-term stability and functional specificity of the regenerated sensory circuits, emphasizing the risk of maladaptive synaptogenesis leading to neuropathic pain. Finally, we contextualize these findings within the challenges of clinical translation, arguing that the efficacy of this approach must be validated in more severe, contusive injury models that better recapitulate the human pathology. This critical analysis aims to frame the essential next steps required to transform this compelling biological discovery into a viable therapeutic strategy.

Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis–mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02193-8.

Previous studies have revealed four distinct epigenetic consensus pineoblastoma (PB) subtypes. The aim of this study was to confirm and further extend their respective genetic underpinnings. Cytogenetics of 83PB were analyzed by high-resolution genome-wide molecular inversion probe analysis and methylation profiling. Seventy-nine cases were screened for mutations by next-generation DNA panel sequencing and for 25 samples mRNA expression was analyzed using NanoString. Additionally, 24 further pineal parenchymal tumors were analyzed. Clinical data of 63 patients was available. Our cohort consisted of 48PB-miRNA1, 19PB-miRNA2, 8PB-MYC/FOXR2, and 8PB-RB1 cases. PB-miRNA subtype tumors had characteristic alterations in microRNA-processing genes; DICER1 mutations (n = 19/64) and homozygous deletions of the DROSHA locus (n = 18/67) were most abundant, followed by DROSHA mutations (n = 12/64). Most frequent cytogenetic aberrations in PB-miRNA cases were chromosome 7 gains (n = 31/67) and chromosome 14 losses (n = 26/67, including 5 cases with copy-neutral LOH). The latter were significantly associated with DICER1 mutations (p < 0.001). OTX2 gain represented the most frequent alteration that occurred in 37/83PB of all subtypes. In the PB-miRNA subtypes we identified cases with polyploid cytogenetics (n = 16/67). In contrast to previous publications, we did not find a difference in survival for the PB-miRNA subtypes, whereas PB-MYC/FOXR2 and PB-RB1 in infants showed a worse outcome. Epigenetically defined PB subtypes are characterized by distinct genetic events. Frequent gains of the oncogene OTX2 indicate a role in the pathogenesis of PB independent of its subtype.

The presence of amyloid and tau pathologies is the pathological hallmark of Alzheimer’s disease (AD). However, the presence of non-demented individuals with sufficient AD pathology indicates that AD-linked pathology does not always lead to dementia. The current view is that a non-demented (ND) individual with sufficient AD pathology represents an individual resilient to AD pathology. To gain insight about resilience to AD pathology, we examined the neuropathology in the brainstem monoaminergic (MAergic) neurons in the Nun Study participants with equally high Braak AD stage (V-VI) with dementia and without clinical dementia. Because MAergic pathology is thought to occur in response to cortical AD pathology, any differences in MAergic pathology between the AD and ND groups with similarly advanced AD pathology could reflect the resilience of MAergic neurons to cortical AD pathology. Examination of Locus Coeruleus (LC) and/or Raphe for the presence of tau pathology showed that, despite the similar forebrain pathology, relative levels of perikaryal and neuritic tau pathology were significantly lower in ND than in AD subjects. The ND subjects exhibit greater pathology than control subjects without AD pathology, indicating that cortical AD pathology does impact subcortical neurons in both AD and ND cases. Significantly, the extent of neurodegenerative pathology in LC and Raphe neurons correlated with cognitive performance in AD cases, while no such correlation was seen in ND cases. Our results show that while cortical AD pathology is associated with increased MAergic neuropathology, quantitative differences in the extent of MAergic pathology in the brainstem may reflect underlying resistance to AD pathology.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02167-w.

Macrophages are crucial for neuroinflammatory responses following traumatic brain injury (TBI), encompassing various subtypes, such as border-associated macrophages (BAMs) that contribute to both brain damage and repair. However, the pathophysiological relevance of subtype-specific molecular markers is poorly understood. This study investigated the role of the BAM marker mannose receptor C-type 1 (MRC1, also known as CD206) during the early phase of TBI using controlled cortical impact (CCI). MRC1 gene expression was up-regulated, peaking between 3 to 7 days post-injury (dpi), and MRC1 protein expression predominantly localized to BAMs. To assess pathophysiological relevance, MRC1-deficient (MRC1-KO) and wild-type littermates (MRC1-WT) were examined following CCI for early neurological deficits, brain structural damage, intracerebral hematoma, and neuroinflammatory marker expression. At 5 dpi, MRC1-KO mice showed increased brain lesion volume and hippocampal neuron loss, with minor differences in neurological deficits compared to MRC1-WT mice. Intracerebral hematoma size increased in male but remained unchanged in female MRC1-KO mice. Immunostaining revealed no genotype-specific effects on GFAP+ astrocytes, while the number of perilesional CD68+ macrophages/microglia were reduced in MRC1-KO mice. Analysis of neuroinflammatory gene markers revealed an overall reduction in MRC1-KO mice. Sex-specific regulation was observed for the M2-like macrophage/microglia marker Arg1, with decreased expression in male and increased expression in female MRC1-KO compared to MRC1-WT mice. In conclusion, lack of MRC1 exacerbated brain tissue damage following experimental TBI. Reduced CD68+ macrophages/microglia and neuroinflammatory marker expression suggests impaired neuroinflammatory response in MRC1-KO, indicating MRC1 expression on BAMs contributes to beneficial early neuroinflammatory response following TBI.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02156-z.

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by a poor prognosis and a manifestation within the first 2 years of life. Genetic hallmark of these tumors is the homozygous inactivation of SMARCB1 or, in some rare cases, of SMARCA4. While heterozygous pathogenic variants of SMARCA4 have been described, inter alia, in the context of other CNS malignancies such as medulloblastoma or glioblastoma, the co-occurrence of pathogenic variants in both, SMARCB1 and SMARCA4, in the same AT/RT has to our knowledge not been reported previously. Liquid biopsy, a rapidly developing and promising technique measuring cell-free DNA (cfDNA) in body fluids such as the cerebrospinal fluid (CSF), offers a minimally invasive method to assess disease status. It has yet to be established as a standard procedure in the diagnostic workup of CNS tumors. We present the case of a three-year-old male diagnosed with an AT/RT that exhibits both biallelic alterations of SMARCB1 due to a frameshift mutation and loss of heterozygosity as well as a heterozygous missense variant in SMARCA4 presenting with early disease progression. We employed liquid biopsy successfully to monitor disease progression throughout treatment and the subsequent relapse. We highlight the ramifications that simultaneous alterations in two chromatin-modifying genes may have for tumor biology and clinical course.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder among the elderly, with limited effective treatments available in clinical practice. Impaired glucose metabolism has long been observed in the brains of AD patients, yet the mechanisms linking metabolic signals to AD pathogenesis remain elusive. Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation. Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD. Genetic dephosphorylation of RNF168 S60 enhances DNA damage response, reduces double-strand breaks (DSBs), and ameliorates learning and memory deficits in Aβ-based mouse models of AD. Mechanistically, RNF168 S60 phosphorylation impairs long-term potentiation (LTP) of mossy fiber-CA3 synapses in the hippocampus. Importantly, genetic dephosphorylation of RNF168 S60 rescues the deficits in Mossy fiber-CA3 synapse LTP, AD-related spine loss and Aβ pathology. Pharmacological inhibition of RNF168 phosphorylation by S6K1 inhibitor PF-4,708,671 alleviated learning and memory deficits. Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation. Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer’s disease.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02115-8.