Huntingtin (htt) is the ancient protein product of the Huntington's disease (HD) gene. The gene contains a polymorphic tri-nucleotide CAG repeat that is translated into polyglutamine amino acid (polyQ) residues in the protein. When this polyQ stretch at the 18 aminoacid (aa) position of the protein expands to over 39 residues, HD occurs, a fatal, genetically dominant, neurodegenerative disease. The CAG repeats are well conserved in deuterostomes, which suggests that they are an ancestral feature retained during the evolution of the protein. Htt carries a number of specific activities in the adult brain; for instance, it promotes transcription of neuronal genes among which is the BDNF, a neurotrophin critical for the survival and activity of cortical and striatal neurons that degenerate in HD. This presentation will highlight the power of combining evolutionary and developmental approaches to the study of the biology of disease-genes and will review the more recent discovery of a function for htt in neuroepithelial stem cells and its implication in HD pathogenesis.
- stem cells
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