Mice with megalencephalic leukoencephalopathy with cysts: A developmental angle

• Published in: Annals of neurology Vol. 77; no. 1; pp. 114 - 131
• Main Authors: Dubey, Mohit, Bugiani, Marianna, Ridder, Margreet C., Postma, Nienke L., Brouwers, Eelke, Polder, Emiel, Jacobs, J. Gerbren, Baayen, Johannes C., Klooster, Jan, Kamermans, Maarten, Aardse, Romy, de Kock, Christiaan P. J., Dekker, Marien P., van Weering, Jan R. T., Heine, Vivi M., Abbink, Truus E. M., Scheper, Gert C., Boor, Ilja, Lodder, Johannes C., Mansvelder, Huibert D., van der Knaap, Marjo S.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-01-2015; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Age Factors; Animals; Animals, Newborn; Astrocytes - metabolism; Astrocytes - pathology; Brain Edema - etiology; Cerebellum - pathology; Cerebral Cortex - cytology; Cerebral Cortex - pathology; Child; Child, Preschool; Cysts; Cysts - genetics; Cysts - metabolism; Cysts - pathology; Cysts - physiopathology; Disease Models, Animal; Gene Expression Regulation, Developmental - genetics; Hereditary Central Nervous System Demyelinating Diseases - genetics; Hereditary Central Nervous System Demyelinating Diseases - metabolism; Hereditary Central Nervous System Demyelinating Diseases - pathology; Hereditary Central Nervous System Demyelinating Diseases - physiopathology; Humans; Infant; Infant, Newborn; Medical research; Membrane Potentials - genetics; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity - genetics; Postural Balance - genetics; Rodents; S100 Calcium Binding Protein beta Subunit - metabolism; Sensation Disorders - genetics; White Matter - metabolism; White Matter - pathology; White Matter - ultrastructure; Young Adult
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24307

Objective
Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic disease characterized by infantile onset white matter edema and delayed onset neurological deterioration. Loss of MLC1 function causes MLC. MLC1 is involved in ion–water homeostasis, but its exact role is unknown. We generated Mlc1‐null mice for further studies.
Methods
We investigated which brain cell types express MLC1, compared developmental expression in mice and men, and studied the consequences of loss of MLC1 in Mlc1‐null mice.
Results
Like humans, mice expressed MLC1 only in astrocytes, especially those facing fluid–brain barriers. In mice, MLC1 expression increased until 3 weeks and then stabilized. In humans, MLC1 expression was highest in the first year, decreased, and stabilized from approximately 5 years. Mlc1‐null mice had early onset megalencephaly and increased brain water content. From 3 weeks, abnormal astrocytes were present with swollen processes abutting fluid–brain barriers. From 3 months, widespread white matter vacuolization with intramyelinic edema developed. Mlc1‐null astrocytes showed slowed regulatory volume decrease and reduced volume‐regulated anion currents, which increased upon MLC1 re‐expression. Mlc1‐null astrocytes showed reduced expression of adhesion molecule GlialCAM and chloride channel ClC‐2, but no substantial changes in other known MLC1‐interacting proteins.
Interpretation
Mlc1‐null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC‐2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC. ANN NEUROL 2015;77:114–131