Genetic defects disrupting glial ion and water homeostasis in the brain

• Published in: Brain pathology (Zurich, Switzerland) Vol. 28; no. 3; pp. 372 - 387
• Main Authors: Min, Rogier, van der Knaap, Marjo S.
• Format: Journal Article
• Language: English
• Published: Switzerland John Wiley & Sons, Inc 01-05-2018; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Astrocytes; Astrocytes - metabolism; Brain - metabolism; Brain damage; Brain Diseases - genetics; Brain Diseases - metabolism; Brain injury; Concentration gradient; Defects; Disease; Dispersal; Edema; Electric contacts; Glial cells; Homeostasis; Humans; Ion Channels - genetics; Ion Channels - metabolism; Ion flux; Ions; Ions - metabolism; leukodystrophies; Leukodystrophy; Magnetic resonance imaging; Mini‐symposium: Leukodystrophies Due to Astroyctic Dysfunction; Mutation; Neuroglia - metabolism; Neurological diseases; Neurons - metabolism; oligodendrocytes; panglial syncytium; Proteins; Substantia alba; Water - metabolism; Water flow; panglial syncytium; homeostasis; oligodendrocytes; astrocytes; leukodystrophies
• ISSN: 1015-6305; 1750-3639
• DOI: 10.1111/bpa.12602

Electrical activity of neurons in the brain, caused by the movement of ions between intracellular and extracellular compartments, is the basis of all our thoughts and actions. Maintaining the correct ionic concentration gradients is therefore crucial for brain functioning. Ion fluxes are accompanied by the displacement of osmotically obliged water. Since even minor brain swelling leads to severe brain damage and even death, brain ion and water movement has to be tightly regulated. Glial cells, in particular astrocytes, play a key role in ion and water homeostasis. They are endowed with specific channels, pumps and carriers to regulate ion and water flow. Glial cells form a large panglial syncytium to aid the uptake and dispersal of ions and water, and make extensive contacts with brain fluid barriers for disposal of excess ions and water. Genetic defects in glial proteins involved in ion and water homeostasis disrupt brain functioning, thereby leading to neurological diseases. Since white matter edema is often a hallmark disease feature, many of these diseases are characterized as leukodystrophies. In this review we summarize our current understanding of inherited glial diseases characterized by disturbed brain ion and water homeostasis by integrating findings from MRI, genetics, neuropathology and animal models for disease. We discuss how mutations in different glial proteins lead to disease, and highlight the similarities and differences between these diseases. To come to effective therapies for this group of diseases, a better mechanistic understanding of how glial cells shape ion and water movement in the brain is crucial.