Ribosomes in RNA Granules Are Stalled on mRNA Sequences That Are Consensus Sites for FMRP Association

Journal article

INTRODUCTION: A murine model mimicking the human osmotic demyelination syndrome (ODS) revealed with histology demyelinated alterations in the relay posterolateral (VPL) and ventral posteromedial (VPM) thalamic nuclei 12 h and 48 h after chronic hyponatremia due to a fast reinstatement of osmolality. Abnormal expression astrocyte markers ALDHL1 and GFAP with immunohistochemistry in these ODS altered zones, prompted aims to verify in both protoplasmic and fibrillar astrocytes with ultrastructure those changes and other associated subcellular modifications.METHOD: This ODS investigation included four groups of mice: Sham (NN; n = 13), hyponatremic (HN; n = 11), those sacrificed 12 h after a fast restoration of normal natremia (ODS12h; n = 6), and mice sacrificed 48 h afterward, or ODS48 h (n = 9). Out of those four groups of mice, with LM and ultrastructure microscopy, the thalamic zones included NN (n = 2), HN (n = 2), ODS12h (n = 3) and ODS48h (n = 3) samples. There, comparisons between astrocytes included organelles, GFAP, and glycogen content changes.RESULTS: Thalamic ODS epicenter damages comprised both protoplasmic (PA) and fibrillar (FA) astrocyte necroses along with those of neuropil destructions and neuron Wallerian demyelinated injuries surrounded by a centrifugal region gradient revealing worse to mild destructions. Ultrastructure aspects of resilient HN and ODS12h PAs disclosed altered mitochondria and accumulations of beta- to alpha-glycogen granules that became eventually captured into phagophores as glycophagosomes in ODS48h. HN and ODS12h time lapse FAs accumulated ribonucleoproteins, cytoskeletal aggresomes, and proteasomes but distant and resilient ODS48h FAs maintained GFAP fibrils along with typical mitochondria and dispersed β-glycogen, including in their neuropil surroundings. Thus, ODS triggered astrocyte injuries that involved both post-transcriptional and post-translational modifications such that astrocytes were unable to use glycogen and metabolites due to their own mitochondria defects while accumulated stalled ribonucleoproteins, cytoskeletal aggresomes were associated with proteasomes and GFAP ablation. Resilient but distant astrocytes revealed restitution of amphibolism where typical carbohydrate storages were revealed along with GFAP, as tripartite extensions supply for restored nerve axon initial segments, neural Ranvier's junctions, and oligodendrocyte -neuron junctional contacts.CONCLUSION: ODS caused astrocyte damage associated with adjacent neuropil destruction that included a regional demyelination caused by a loss of dispatched energetic and metabolic exchanges within the injured region, bearing proportional and collateral centrifugal injuries, which involved reactive repairs time after rebalanced osmolarity.

Authors: Anadolu, MN; Sun, J; Kailasam, S; Chalkiadaki, K; Krimbacher, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Society for Neuroscience
• Journal: The Journal of Neuroscience
• Volume: 43
• Issue: 14
• Pages: 2440-2459
• Publication date: 2023-02-27
• DOI: 10.1523/jneurosci.1002-22.2023
• EISSN: 1529-2401
• ISSN: 0270-6474
• Language: English
• Keywords: Gene; Translation (biology); Ribosome; Cell biology; Ribosome profiling; RNA; Molecular biology; Biochemistry; Protein biosynthesis; Messenger RNA; Eukaryotic Ribosome; Biology; Polysome