Genetic ablation of Nrf2/antioxidant response pathway in Alexander disease mice reduces hippocampal gliosis but does not impact survival.

[alexander disease]

In Alexander disease (AxD ) the presence of mutant glial fibrillary acidic protein (GFAP ), the major intermediate filament of astrocytes , triggers protein aggregation , with marked induction of a stress response mediated by the transcription factor , Nrf 2 . To clarify the role of Nrf 2 in AxD , we have crossed Gfap mutant and transgenic mouse models into an Nrf 2 null background . Deletion of Nrf 2 eliminates the phase II stress response normally present in mouse models of AxD , but causes no change in body weight or lifespan , even in a severe lethal model . AxD astrocytes without Nrf 2 retain features of reactivity , such as expression of the endothelin-B receptor , but have lower Gfap levels , a decrease in p 62 protein and reduced iron accumulation , particularly in hippocampus . Microglial activation , indicated by Iba 1 expression , is also diminished . Although the Nrf 2 response is generally considered beneficial , these results show that in the context of AxD , loss of the antioxidant pathway has no obvious negative effects , while actually decreasing Gfap accumulation and pathology . Given the attention Nrf 2 is receiving as a potential therapeutic target in AxD and other neurodegenerative diseases , it will be interesting to see whether induction of Nrf 2 , beyond the endogenous response , is beneficial or not in these same models .

Diseases
Validation

Diseases presenting "potential therapeutic target" symptom

alexander disease

canavan disease

dedifferentiated liposarcoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

heparin-induced thrombocytopenia

krabbe disease

liposarcoma

lymphangioleiomyomatosis

primary effusion lymphoma

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

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