Prof. Nicole Wolf
Neuroscience Symposium
Neuroscience Symposium
Host: Prof. Nicole Wolf
On behalf of Prof. Dr. Marjo van der Knaap
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers. e-mail: n.wolf@amsterdamumc.nl
The Guest Speaker:
Javier Triñanes Ramos, PhD
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, 1105 AZ, The Netherlands.
Title: Cell-specific Eif2b5 mutant mice: novel insights into roles of macroglia in Vanishing White Matter.
Abstract:
Vanishing white matter (VWM) is a leukodystrophy caused by mutations in any of the genes encoding the subunits of the eukaryotic translation initiation factor 2B (eIF2B), a central factor in mRNA translation initiation and critical for the regulation of translation rates during the integrated stress response (ISR). VWM is characterized by chronic and stress-provoked acute episodic motor and cognitive decline leading to premature death. The neuropathology shows selective white matter involvement, with dysmorphic and immature astrocytes, impaired reactive astrogliosis, and oligodendrocytes showing increased expression of immaturity and proliferation markers. White matter cells also show increased expression of ISR genes. Neurons are much less affected, although not completely normal. Astrocytes have been previously described as key drivers of the disease, however the relative contribution of each cell type to the development of VWM has remained unclear.
We generated astrocyte-, oligodendrocyte-, and neuron-specific Eif2b5 conditional mouse lines to determine the role of each mutant cell type in the onset and development of the disease. We evaluated motor performance, white matter pathology and the expression of myelin-related proteins. We analyzed astrocytes and oligodendrocytes density, maturity, morphology, proliferation, and apoptosis. We investigated the expression of the ISR genes and proteins.
Our results show that contrary to the previous hypothesis, oligodendrocytes are the major contributors to the development of ataxia, but astrocyte-specific Eif2b5 conditional mice display several histological and molecular key features of VWM. Mutant neurons contribute little to VWM disease development. Our findings highlight a complex effect of Eif2b5 mutations in different macroglial cell types leading to the clinical and neuropathological characteristics of VWM. The view of a single cell population being responsible for the onset and development of VWM needs to be replaced by the concept of VWM as a glial disease.
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