Glial Dysfunction in Ataxia Telangiectasia


Principal Investigator: Margot Mayer Proschel
Abstract: This proposal is focused on defining and characterizing a potentially novel cellular target that is affected in the genetic disease Ataxia telangiectasia (AT). AT belongs to a class of neurological disorders in which perinatal development can appear to progress normally, but in which increasingly severe dysfunction eventually emerges. Symptoms include sensitivity to ionizing radiation, oculomotor apraxia, chorea, athetosis, dystonia, peripheral neuropathy, infertility, translocations of chromosomes 7 and 14, underdeveloped thymus, and increased risk of neoplasms leading to poor quality of life. Most patients die during the second or early third decade of life and while the genetic lesions responsible for AT (called ATM, for AT-mutated) were first identified in 1988, no known therapy has been identified. While the majority of studies are focused on the biology of the primary pathological identifiable target, the progressive degeneration of cerebellar neurons, our studies revealed dysfunction in astrocytes derived from the CNS of a mouse model of AT. Our studies on ATM deficient astrocytes show that a number of critical functions are impaired in mutant astrocytes that specifically reside in the cerebellum, the major site of pathology. We also show in co-cultures experiments that AT-deficient cerebellar neurons shows signs of degeneration and growth impairment, while normal wildtype astrocytes seem to be able to maintain the integrity of mutant neurons and support their survival. These result suggest that the astrocytic dysfunction in AT might be a significant contributor to the neuronal pathology. This proposal extends upon our preliminary observations and we propose to test in Aim 1 whether and to what degree astrocytes derived from various regions of ATM brains are compromised in critical functions, including control of oxidative stress, production of growth factors and regulation of glutamate concentrations in the extracellular environment. In Aim 2 we will test the hypothesis that the defect in the astrocyte population is already occurring on the stage of the precursor cells that give rise to astrocytes and is hence a cell-intrinsic rather than regionally imposed dysfunction. Finally, we extend in Aim 3 our co-culture experiments to determine strategies that can be used to correct astrocyte function and rescue neuronal cells from degeneration. Such correction will examine three therapeutically relevant possibilities: growth of ATM-derived cells in the presence of varying proportions of normal astrocytes and of conditioned medium derived from normal astrocytes, genetic correction of abnormalities in ATM-derived cerebellar astrocytes and pharmacological manipulation of astrocytes to reduce their oxidative stress. The components of this application should provide clear information on whether astrocytes contribute to the neuronal degeneration. If restoration of astrocytic function proves beneficial, this would provide an entirely new strategy to the eventual treatment of AT. This proposal is focused on the characterization of a novel cellular target we have identified that is affected in the genetic disease Ataxia telangiectasia (AT), which belongs to a class of fatal neurological disorders with no known therapy. We propose experiments that would provide an entirely new strategy to the treatment of AT.
Funding Period: 2008-04-01 - 2010-03-31
more information: NIH RePORT