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Bystander Diseases: Astrocytic Dysfunction as a Causal Mechanism in Neurological Disease

Project Overview

While it has long been recognized that astrocytes play multiple critical roles in the regulation of normal CNS function, the possibility that astrocyte-specific dysfunction might cause diseases that manifest as pathologies of oligodendrocytes or neurons is a relatively recent idea. One of the first discoveries revealing this novel pathogenic mechanism was the finding that a disease that manifests as degeneration of myelinated tracts of the CNS might be caused by a defect in the generation of astrocytes by glial precursor cells.

The discoveries that developmental maladies associated with thyroid hormone deficiency or iron deficiency might be precursor cell diseases led to the question of whether there were also genetic precursor cell diseases. This question was addressed under the leadership of Chris Pröschel, and were focused on a genetic disease called Vanishing White Matter (VWM) disease, one of the most prevalent of leukodystrophies. Children with VWM appear normal at birth, with neurological deterioration beginning in late infancy or early childhood. This disease, which associated with loss of myelin in the brains of affected individuals, would have been expected to be associated with abnormalities in oligodendrocyte function. Instead, studies on precursor cells isolated from the CNS of a child who had died of this disease revealed that these cells were defective in their ability to generate astrocytes (Dietrich et al., 2005).

The discoveries that VWM neural precursor cells were defective in their ability to generate astrocytes, and that astrocyte generation from these precursor cells was defective, suggested the intriguing new concept that defects in astrocyte function could cause disease in which the primary pathology suggested that the defect would be in a different cell type. Thus, these studies not only provide an example of a genetic precursor cell disease but also provided one of the first examples indicating that astrocyte dysfunction could cause a bystander disease (by which we mean a disease in which the primary lesion observed in pathological analysis is caused by a primary dysfunction in a separate cell type).

The discovery that there is a defect in astrocyte generation in VWM raise the possibility that it is astrocyte replacement therapies (see section on glial repair strategies) that will be critical in developing treatments for this fatal disease.

Since this publication, the concept that astrocyte dysfunction may be central to the understanding of CNS diseases in which the primary pathological changes observed appear to involve other cell types has been extended to include amyotrophic lateral sclerosis caused by mutation of superoxide dismutase-1, and spincocerebellar ataxia 7, with ongoing studies conducted in the laboratory of Margot Mayer-Pröschel further extending this work to include ataxia telangiectasia.

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Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., and Proschel, C. (2005). EIF2B5 mutations compromise GFAP(+) astrocyte generation in vanishing white matter leukodystrophy. Nat. Med. 11, 277-283. link

Contact

Mark D. Noble
University of Rochester
Box 633
601 Elmwood Ave.
Rochester, NY 14642
Office: MRB 2-9625
+1-585-273-1448 mark_noble@urmc.
rochester.edu