Phenotypic conversions of "protoplasmic" to "reactive" astrocytes in Alexander disease.

[alexander disease]

Alexander Disease (AxD ) is a primary disorder of astrocytes , caused by heterozygous mutations in GFAP , which encodes the major astrocyte intermediate filament protein , glial fibrillary acidic protein (GFAP ). Astrocytes in AxD display hypertrophy , massive increases in GFAP , and the accumulation of Rosenthal fibers , cytoplasmic protein inclusions containing GFAP , and small heat shock proteins . To study the effects of GFAP mutations on astrocyte morphology and physiology , we have examined hippocampal astrocytes in three mouse models of AxD , a transgenic line (GFAP (Tg )) in which the normal human GFAP is expressed in several copies , a knock-in line (Gfap (+/R 236 H )) in which one of the Gfap genes bears an R 236 H mutation , and a mouse derived from the mating of these two lines (GFAP (Tg ); Gfap (+/R 236 H )). We report changes in astrocyte phenotype in all lines , with the most severe in the GFAP (Tg );Gfap (+/R 236 H ), resulting in the conversion of protoplasmic astrocytes to cells that have lost their bushy-like morphology because of a reduction of distal fine processes , and become multinucleated and hypertrophic . Astrocytes activate the mTOR cascade , acquire CD 44 , and lose GLT-1 . The altered astrocytes display a microheterogeneity in phenotypes , even neighboring cells . Astrocytes also show diminished glutamate transporter current , are significantly depolarized , and not coupled to adjacent astrocytes . Thus , the accumulation of GFAP in the AxD mouse astrocytes initiates a conversion of normal , protoplasmic astrocytes to astrocytes that display severely "reactive " characteristics , many of which may be detrimental to neighboring neurons and oligodendrocytes .

Diseases
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Diseases presenting "a reduction of distal fine processes" symptom

alexander disease

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