Axonal abnormalities in vanishing white matter

Abstract

ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter.MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single‐ and double‐mutant mice and patient brain tissue. In addition, astrocyte‐forebrain co‐culture studies were performed.ResultsIn the corpus callosum of Eif2b5‐mutant mice, myelin sheath thickness, axonal diameter, and G‐ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G‐ratio in Eif2b5‐mutant mice. In more severely affected Eif2b4‐Eif2b5 double‐mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5‐mutant mice. Co‐cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal.InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

“…32 This confirms earlier findings that neuronal dysfunction in VWM should not be overlooked. 33 Our human transcriptome data furthermore showed a number of DEGs involved in mitochondrial functioning, including CTGF, CYP1B1, NTRK2, CNR1, TBX2, and MT2A. CNR1, driven by PAX3 expression, 34 both of which are upregulated in VWM human WM astrocytes, is known to regulate mitochondrial functioning and protects against neuroinflammation resulting from oxidative stress.…”

“…This induces glycolytic upregulation of ATP and lactate in astrocytes, as well as regulation of the extracellular potassium concentration, because the ATP-driven Na + pump actively pumps potassium into the cells. 33 Our human transcriptome data furthermore showed a number of DEGs involved in mitochondrial functioning, including CTGF, CYP1B1, NTRK2, CNR1, TBX2, and MT2A. 31 Interestingly, VWM human WM astrocytes showed increased AQP4 levels.…”

Vanishing white matter: a leukodystrophy due to astrocytic dysfunction

“…In the white matter of VWM mouse models, axons are thinner and the percentage of thin axons is higher than in controls . Myelin sheath thickness, axonal diameter and G‐ratio are initially normal, but later axons become thinner and the G‐ratio is abnormally low . These changes co‐vary with disease severity.…”

“…Additionally, an increased percentage of thin, unmyelinated axons and increased axonal density are found. Co‐cultures of neurons with astrocytes show that mutant astrocytes induce increased axonal density, also of control neurons, whereas control astrocytes induce normal axonal density, also of mutant neurons . In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities are notably minimal .…”

Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

“…Until now, the pathomechanisms of VWM have remained unclear. Available evidence indicates primary astrocyte involvement, secondary impediment of oligodendrocyte maturation and function, and negligible neuronal involvement (3,10,41,42).…”