Linked Life Data

16014634

Source:http://linkedlifedata.com/resource/pubmed/id/16014634

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2005-8-2
pubmed:abstractText
Alexander disease is a fatal neurodegenerative disorder resulting from missense mutations of the intermediate filament protein, GFAP. The pathological hallmark of this disease is the formation of cytoplasmic protein aggregates within astrocytes known as Rosenthal fibers. Transgenic mice engineered to over-express wild-type human GFAP develop an encephalopathy with identical aggregates, suggesting that elevated levels of GFAP in addition to mutant protein contribute to the pathogenesis of this disorder. To study further the effects of elevated GFAP and Rosenthal fibers per se, independent of mutations, we performed gene expression analysis on olfactory bulbs of transgenic mice at two different ages to follow the progression of pathology. The expression profiles reveal a stress response that includes genes involved in glutathione metabolism, peroxide detoxification and iron homeostasis. Many of these genes are regulated by the transcription factor Nfe2l2, which is also increased in expression at 3 weeks. An immune-related response occurs with activation of cytokine and cytokine receptor genes, complement components and acute phase response genes. These transcripts are further elevated with age, with additional induction of macrophage-specific markers such as Mac1 and CD68, suggesting activation of microglia. At 4 months, decreased expression of genes for microtubule-associated proteins, vesicular trafficking proteins and neurotransmitter receptors becomes apparent. Interneuron-specific transcription factors including Dlx family members and Pax6 are downregulated as well as Gad1 and Gad2, suggesting impairment of GABAergic granule cells. Together, these data implicate an initial stress response by astrocytes, which results in the activation of microglia and compromised neuronal function.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0964-6906
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
14
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2443-58
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Gene expression analysis in mice with elevated glial fibrillary acidic protein and Rosenthal fibers reveals a stress response followed by glial activation and neuronal dysfunction.
pubmed:affiliation
Wisman Center, University of Wisconsin, Madison, WI 53705, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural