Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

We present a case report on an older woman with unspecific symptoms and predominant long-term gastrointestinal disturbances, acute overall health deterioration with loss of autonomy for daily activities, and cognitive impairment. Autopsy revealed the presence of alpha-synuclein deposits spread into intestinal mucosa lesions, enteric plexuses, pelvic and retroperitoneal nerves and ganglia, and other organs as well as Lewy pathology in the central nervous system (CNS). Moreover, we isolated norovirus from the patient, indicating active infection in the colon and detected colocalization of norovirus and alpha-synuclein in different regions of the patient’s brain. In view of this, we report a concomitant norovirus infection with synthesis of alpha-synuclein in the gastrointestinal mucosa and Lewy pathology in the CNS, which might support Braak’s hypothesis about the pathogenic mechanisms underlying synucleinopathies.

Brain aging consists of a progressive loss of functional capacities, which is associated with a progressive cognitive decline and can lead to neurodegenerative diseases. Studies comparing the underlying molecular mechanisms of the human hippocampus between young and older adults remain scarce. In our study, we completed a transcriptomic analysis from hippocampal samples of different ages and performed 2 complementary analyses. A comparison between young and old groups revealed a set of genes differentially expressed in aged individuals linked to inflammation and immune system pathways, DNA repair, metabolism, or neural activity. Correlation analysis showed that the expression of an additional subset of 6 genes was associated with chronological aging. Among them, further analysis identified RAD23B as the most significant gene with a negative correlation of its mRNA and protein expression with age in the human hippocampus. Its expression was even lower in patients with Alzheimer's disease. RAD23B was mostly expressed in neurons and astrocytes, where studies in human primary cultures uncovered that it is required for cell survival and function. In summary, these results unravel dynamic gene expression changes that distinguish young from older adults and identify RAD23B as a putative biomarker and regulator of cell aging in the brain.

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