Suppression of GFAP toxicity by alphaB-crystallin in mouse models of Alexander disease.

[alexander disease]

Alexander disease (AxD ) is a primary disorder of astrocytes caused by dominant mutations in the gene for glial fibrillary acidic protein (GFAP ). These mutations lead to protein aggregation and formation of Rosenthal fibers , complex astrocytic inclusions that contain GFAP , vimentin , plectin , ubiquitin , Hsp 27 and alphaB-crystallin . The small heat shock protein alphaB-crystallin (Cryab ) regulates GFAP assembly , and elevation of Cryab is a consistent feature of AxD ; however , its role in Rosenthal fibers and AxD pathology is not known . Here , we show in AxD mouse models that loss of Cryab results in increased mortality , whereas elevation of Cryab rescues animals from terminal seizures . When mice with Rosenthal fibers induced by over-expression of GFAP are crossed into a Cryab-null background , over half die at 1 month of age . Restoration of Cryab expression through the GFAP promoter reverses this outcome , showing the effect is astrocyte-specific . Conversely , in mice engineered to express both AxD -associated mutations and elevated GFAP , which despite natural induction of Cryab also die at 1 month , transgenic over-expression of Cryab results in a markedly reduced CNS stress response , restores expression of the glutamate transporter Glt 1 (EAAT 2 ) and protects these animals from death . In its most common form , AxD is a devastating neurodegenerative disease , with early onset , characterized by seizures , spasticity and developmental delays , ultimately leading to death . Cryab plays a critical role in tempering AxD pathology and should be investigated as a therapeutic target for this and other diseases with astropathology .

Diseases
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Diseases presenting "complex astrocytic inclusions" symptom

alexander disease

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