PRMT1 driven PTX3 regulates ferritinophagy in glioma.

Mutations in the Krebs cycle enzyme IDH1 (isocitrate dehydrogenase (NADP(+)) 1) are associated with better prognosis in gliomas. Though IDH1 mutant (IDH1R132H) tumors are characterized by their antiproliferative signatures maintained through hypermethylation of DNA and chromatin, mechanisms affecting cell death pathways in these tumors are not well elucidated. On investigating the crosstalk between the IDH1 mutant epigenome, ferritinophagy and inflammation, diminished expression of PRMT1 (protein arginine methyltransferase 1) and its associated asymmetric dimethyl epigenetic mark H4R3me2a was observed in IDH1R132H gliomas. Reduced expression of PRMT1 was concurrent with diminished levels of PTX3, a key secretory factor involved in cancer-related inflammation. Lack of PRMT1 H4R3me2a in IDH1 mutant glioma failed to epigenetically activate the expression of PTX3 with a reduction in YY1 (YY1 transcription factor) binding on its promoter. Transcriptional activation and subsequent secretion of PTX3 from cells was required for maintaining macroautophagic/autophagic balance as pharmacological or genetic ablation of PTX3 secretion in wild-type IDH1 significantly increased autophagic flux. Additionally, PTX3-deficient IDH1 mutant gliomas exhibited heightened autophagic signatures. Furthermore, we demonstrate that the PRMT1-PTX3 axis is important in regulating the levels of ferritin genes/iron storage and inhibition of this axis triggered ferritinophagic flux. This study highlights the conserved role of IDH1 mutants in augmenting ferritinophagic flux in gliomas irrespective of genetic landscape through inhibition of the PRMT1-PTX3 axis. This is the first study describing ferritinophagy in IDH1 mutant gliomas with mechanistic details. Of clinical importance, our study suggests that the PRMT1-PTX3 ferritinophagy regulatory circuit could be exploited for therapeutic gains.Abbreviations: 2-HG: D-2-hydroxyglutarate; BafA1: bafilomycin A1; ChIP: chromatin immunoprecipitation; FTH1: ferritin heavy chain 1; FTL: ferritin light chain; GBM: glioblastoma; HMOX1/HO-1: heme oxygenase 1; IHC: immunohistochemistry; IDH1: isocitrate dehydrogenase(NADP(+))1; MDC: monodansylcadaverine; NCOA4: nuclear receptor coactivator 4; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; PTX3/TSG-14: pentraxin 3; PRMT: protein arginine methyltransferase; SLC40A1: solute carrier family 40 member 1; Tan IIA: tanshinone IIA; TCA: trichloroacetic acid; TEM: transmission electron microscopy; TNF: tumor necrosis factor.

Histological changes in thalamus in short term survivors following traumatic brain injury: an autopsy study.

BACKGROUND: Severe traumatic brain injury (TBI) is a major cause of morbidity and mortality. Reduction of thalamic volumes were seen in upto 80% of patients who survived for more than 3 months after TBI. However, the same may not be true in patients who died earlier following TBI. AIMS: To to study the thalamus for evidence of any injury in short term survivors of TBI (<5 days) using immunohistochemistry to look for evidence of acute thalamic injury. MATERIALS AND METHODS: A cross sectional prospective study was done in which autopsy specimens of short term survivors of TBI (<5 days) were studied for histopathological changes. RESULTS: A total of 16 patients with a mean age of 37.8 years were included in the study. CT scan revealed acute subdural haematoma in 10, contusions in 4 patients, extradural haematoma and depressed fracture in 1 each, and diffuse axonal injury in 1 patient. Seven patients required surgery in the form of a decompressive hemicraniectomy. The histopathological analysis of the bilateral thalami showed evidence of congestion of the cerebral capillaries in 8 patients. Axonal retraction balls were seen in 8 patients, myelin breakdown products were seen in 14 patients and axonal swelling was seen in 14 patients. CONCLUSIONS: Thalamic injury is universal in the setting of severe TBI in patients who have decreased survival and may be a significant factor for the poor outcome in these patients.