title: Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy.
abstract: We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of Nrl and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function.
authors.affiliation: Department of Molecular Pathology, Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP10142, 67404 Illkirch Cédex, CU de Strasbourg, France. merienne@igbmc.u-strasbg.fr
authors.forename: Karine
authors.initials: K
authors.lastname: Merienne
authors.forename: James
authors.initials: J
authors.lastname: Friedman
authors.forename: Masayuki
authors.initials: M
authors.lastname: Akimoto
authors.forename: Gretta
authors.initials: G
authors.lastname: Abou-Sleymane
authors.forename: Chantal
authors.initials: C
authors.lastname: Weber
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Yvon
authors.initials: Y
authors.lastname: Trottier
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; D009419:Nerve Tissue Proteins; C084884:Nrl protein, mouse; D010455:Peptides; D018808:Transcription Factor AP-1; C097188:polyglutamine; D048031:JNK Mitogen-Activated Protein Kinases