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Hum Mol Genet. 2006 Mar 1;15(5):691-703. Epub 2006 Jan 24.

Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program.

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Department of Molecular Pathology, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, BP10142, 67404 Illkirch Cédex, CU de Strasbourg, France.


Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) belong to a group of inherited neurodegenerative diseases caused by polyglutamine (polyQ) expansion in corresponding proteins. Transcriptional alteration is a unifying feature of polyQ disorders; however, the relationship between polyQ-induced gene expression deregulation and degenerative processes remains unclear. R6/2 and R7E mouse models of HD and SCA7, respectively, present a comparable retinal degeneration characterized by progressive reduction of electroretinograph activity and important morphological changes of rod photoreceptors. The retina, which is a simple central nervous system tissue, allows correlating functional, morphological and molecular defects. Taking advantage of comparing polyQ-induced degeneration in two retina models, we combined gene expression profiling and molecular biology techniques to decipher the molecular pathways underlying polyQ expansion toxicity. We show that R7E and R6/2 retinal phenotype strongly correlates with loss of expression of a large cohort of genes specifically involved in phototransduction function and morphogenesis of differentiated rod photoreceptors. Accordingly, three key transcription factors (Nrl, Crx and Nr2e3) controlling rod differentiation genes, hence expression of photoreceptor specific traits, are down-regulated. Interestingly, other transcription factors known to cause inhibitory effects on photoreceptor differentiation when mis-expressed, such as Stat3, are aberrantly re-activated. Thus, our results suggest that independently from the protein context, polyQ expansion overrides the control of neuronal differentiation and maintenance, thereby causing dysfunction and degeneration.

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