Astrocytic TDP-43 pathology in Alexander disease.

[alexander disease]

Alexander disease (AxD ) is a rare neurodegenerative disorder characterized pathologically by the presence of eosinophilic inclusions known as Rosenthal fibers (RFs ) within astrocytes , and is caused by dominant mutations in the coding region of the gene encoding glial fibrillary acidic protein (GFAP ). GFAP is the major astrocytic intermediate filament , and in AxD patient brain tissue GFAP is a major component of RFs . TAR DNA binding protein of 43 kDa (TDP-43 ) is the major pathological protein in almost all cases of the neurodegenerative disease amyotrophic lateral sclerosis (ALS ) and âˆ¼ 50 % of frontotemporal lobar degeneration (FTLD ), designated as FTLD-TDP . In ALS and FTLD-TDP , TDP-43 becomes insoluble , ubiquitinated , and pathologically phosphorylated and accumulates in cytoplasmic inclusions in both neurons and glia of affected brain and spinal cord regions . Previously , TDP-43 was detected in RFs of human pilocytic astrocytomas ; however , involvement of TDP-43 in AxD has not been determined . Here we show that TDP-43 is present in RFs in AxD patient brains , and that insoluble phosphorylated full-length and high molecular weight TDP-43 accumulates in white matter of such brains . Phosphorylated TDP-43 also accumulates in the detergent-insoluble fraction from affected brain regions of Gfap (R 236 H /+) knock-in mice , which harbor a GFAP mutation homologous to one that causes AxD in humans , and TDP-43 colocalizes with astrocytic RF pathology in Gfap (R 236 H /+) mice and transgenic mice overexpressing human wild-type GFAP . These findings suggest common pathogenic mechanisms in ALS , FTLD , and AxD , and this is the first report of TDP-43 involvement in a neurological disorder primarily affecting astrocytes .

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Diseases presenting "rare neurodegenerative disorder" symptom

alexander disease

cadasil

x-linked adrenoleukodystrophy

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