title: Osmotic Stress-Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment.
abstract: Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.
authors.affiliation: Faculty of Medicine, Research Unit on Hydromineral Metabolism, fgankamk@ulb.ac.be guy.decaux@skynet.be.|Faculty of Medicine, Laboratory of Histology and Neuroanatomy and Neuropathology, and.|Service de Néphrologie, EpiCURA Ath, Ath, Belgium; and.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gankam-Kengne
authors.affiliation: Faculty of Medicine, Research Unit on Hydromineral Metabolism.|Faculty of Medicine, Laboratory of Histology and Neuroanatomy and Neuropathology, and.|Hopital Erasme, Service de Médecine Interne générale, Université Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Bruno S
authors.initials: BS
authors.lastname: Couturier
authors.affiliation: Faculty of Medicine, Research Unit on Hydromineral Metabolism.|Service de Médecine Interne Générale, Hopitaux Iris Sud site Molière, Bruxelles, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Soupart
authors.affiliation: Faculty of Medicine, Laboratory of Histology and Neuroanatomy and Neuropathology, and.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Brion
authors.affiliation: Faculty of Medicine, Research Unit on Hydromineral Metabolism, fgankamk@ulb.ac.be guy.decaux@skynet.be.|Hopital Erasme, Service de Médecine Interne générale, Université Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Decaux
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000209:etiology*; D003711:Demyelinating Diseases / Q000209:etiology*; D059865:Endoplasmic Reticulum Stress; D006706:Homeostasis; D007010:Hyponatremia / Q000628:therapy*; D008297:Male; D009457:Neuroglia; D009997:Osmotic Pressure; D066263:Protein Aggregation, Pathological / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
keywords: hyponatremia; malfolding proteins; osmolality