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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxin-7
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Base Sequence
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / metabolism
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Disease Models, Animal
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Female
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JNK Mitogen-Activated Protein Kinases / genetics*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Mice, Transgenic
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Molecular Sequence Data
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Nerve Degeneration / metabolism
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Nerve Degeneration / pathology
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Nerve Degeneration / physiopathology
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Peptides / genetics*
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Peptides / metabolism
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Phosphorylation
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Retinal Diseases / genetics*
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Retinal Diseases / metabolism*
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Retinal Diseases / pathology
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Retinal Rod Photoreceptor Cells / pathology
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Retinal Rod Photoreceptor Cells / physiology
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transgenes / physiology
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Up-Regulation / physiology
Substances
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Ataxin-7
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Atxn7 protein, mouse
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Basic-Leucine Zipper Transcription Factors
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Eye Proteins
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Nerve Tissue Proteins
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Nrl protein, mouse
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Peptides
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Transcription Factor AP-1
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polyglutamine
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JNK Mitogen-Activated Protein Kinases