Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

Abstract

Leukodystrophies are often devastating diseases, presented with progressive clinical signs as spasticity, ataxia and cognitive decline, and lack proper treatment options. New therapy strategies for leukodystrophies mostly focus on oligodendrocyte replacement to rescue lack of myelin in the brain, even though disease pathology also often involves other glial cells and the spinal cord. In this study we investigated spinal cord pathology in a mouse model for Vanishing White Matter disease (VWM) and show that astrocytes in the white matter are severely affected. Astrocyte pathology starts postnatally in the sensory tracts, followed by changes in the astrocytic populations in the motor tracts. Studies in post‐mortem tissue of two VWM patients, a 13‐year‐old boy and a 6‐year‐old girl, confirmed astrocyte abnormalities in the spinal cord. For proper development of new treatment options for VWM and, possibly, other leukodystrophies, future studies should investigate spinal cord involvement.

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

“…8,11 The presented astrocytes derived from mouse and human iPSCs recapitulate earlier findings in mouse and human, such as increased proliferation, morphological abnormalities, and induction of decreased oligodendrocyte maturation. 8,11 The presented astrocytes derived from mouse and human iPSCs recapitulate earlier findings in mouse and human, such as increased proliferation, morphological abnormalities, and induction of decreased oligodendrocyte maturation.…”

“…8,11 The presented astrocytes derived from mouse and human iPSCs recapitulate earlier findings in mouse and human, such as increased proliferation, morphological abnormalities, and induction of decreased oligodendrocyte maturation. 8,11 To our knowledge, we are the first to present VWM iPSC models involving subtype-specific astrocytes. 8,11 To our knowledge, we are the first to present VWM iPSC models involving subtype-specific astrocytes.…”

“…8,10 Interestingly, WM astrocytes are more vulnerable to VWM mutations than GM astrocytes, as indicated before in patient tissue. 8,11 To our knowledge, we are the first to present VWM iPSC models involving subtype-specific astrocytes.…”

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

“…Astrocytes play a central role in pathology in VWM (Bugiani et al, 2011;Leferink et al, 2017). The presented astrocytes derived from miPSCs and hiPSCs recapitulate earlier findings in mouse and human, such as increased proliferation, morphological abnormalities and induction of decreased OPC maturation (Bugiani et al, 2011;Dooves et al, 2016).…”

“…This is especially clear in Vanishing White Matter (VWM), one of the more prevalent leukodystrophies, which is caused by mutations in the EIF2B1-5 genes and for which no treatment is available (Van der Knaap, 2016). Previous studies showed that white matter astrocytes are selectively affected in VWM, while grey matter astrocytes are spared (Bugiani et al, 2011;Bugiani et al, 2013;Dooves et al, 2016;Leferink et al, 2017). These findings indicate that it is essential to generate iPSC models for disease-related astrocyte subtypes.…”