Protein misfolding and oxidative stress promote glial-mediated neurodegeneration in an Alexander disease model.

[alexander disease]

Although alterations in glial structure and function commonly accompany death of neurons in neurodegenerative diseases , the role glia play in modulating neuronal loss is poorly understood . We have created a model of Alexander disease in Drosophila by expressing disease-linked mutant versions of glial fibrillary acidic protein (GFAP ) in fly glia . We find aggregation of mutant human GFAP into inclusions bearing the hallmarks of authentic Rosenthal fibers . We also observe significant toxicity of mutant human GFAP to glia , which is mediated by protein aggregation and oxidative stress . Both protein aggregation and oxidative stress contribute to activation of a robust autophagic response in glia . Toxicity of mutant GFAP to glial cells induces a non-cell-autonomous stress response and subsequent apoptosis in neurons , which is dependent on glial glutamate transport . Our findings thus establish a simple genetic model of Alexander disease and further identify cellular pathways critical for glial-induced neurodegeneration .

Diseases
Validation

Diseases presenting "neuronal loss" symptom

22q11.2 deletion syndrome

alexander disease

locked-in syndrome

pyruvate dehydrogenase deficiency

This symptom has already been validated