Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations

• DOI: 10.1093/hmg/dds032
• Publication Date: 2012-02-11T02:07:09Z
• Authors: Angela Lanciotti; Maria S. Brignone; Paola Molinari; Sergio Visentin; Chiara De Nuccio; Gianfranco Macchia; Chiara Aiello; Enrico Bertini; Francesca Aloisi; Tamara C. Petrucci; Elena Ambrosini
• Keywords: TRPV4; Aquaporin 4; Neuroglia

Megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare leukodystrophy characterized by macrocephaly, fluid and myelin vacuolation, has been linked to mutations in the MLC1 gene. This gene encodes membrane protein that is highly expressed astrocytes. Based on MLC pathological features, it was proposed astrocyte-mediated defects ion homeostasis could account for alterations observed MLC-affected brains. However, role of effects astrocyte osmoregulatory functions have still be demonstrated. Using human astrocytoma cells stably overexpressing wild-type or three known MLC-associated mutations, we investigated involvement reaction osmotic changes using biochemical, dynamic video imaging immunofluorescence techniques. We found overexpressed mainly localized plasma membrane, part Na,K-ATPase-associated molecular complex includes potassium channel Kir4.1, syntrophin aquaporin-4 functionally interacts calcium permeable TRPV4 (transient receptor potential vanilloid-4 cation channel) which mediates swelling-induced cytosolic increase volume recovery response hyposmosis. Pathological cause expression intracellular localization as well altering interactions Na,K-ATPase abolishing influx induced hyposmosis treatment agonist 4αPDD. These data demonstrate, first time, plays osmo-homeostasis dynamics may contribute pathogenesis.