Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1

• Published in: Nature neuroscience Vol. 3; no. 2; pp. 157 - 163
• Main Authors: Zoghbi, Huda Y, Lin, Xi, Antalffy, Barbara, Kang, Dongcheul, Orr, Harry T
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.02.2000
• Subjects: alpha 1-Antichymotrypsin - metabolism; Amino Acid Transport System X-AG; Animals; Ataxia; Ataxin-1; Ataxins; Brain - enzymology; Calcium Channels - metabolism; Calcium-Transporting ATPases - metabolism; Cloning; Cloning, Molecular; Diagnosis; Disease Models, Animal; Down-Regulation - genetics; Gene expression; Gene Expression Regulation; Genetic aspects; Genetic regulation; Glutamate Plasma Membrane Transport Proteins; Glutamine; Humans; Hybridization; Inositol 1,4,5-Trisphosphate Receptors; Inositol Polyphosphate 5-Phosphatases; Localization; Medicine; Mice; Mice, Transgenic; Molecular Sequence Data; movement disorders; Mutation; Nerve Tissue Proteins; Neurons - enzymology; Nuclear Proteins; Organ Specificity; Pathogenesis; Pathology; Peptides - genetics; Phosphoric Monoester Hydrolases - metabolism; Physiological aspects; polyglutamine; Protein Methyltransferases - biosynthesis; Protein Methyltransferases - chemistry; Protein Methyltransferases - genetics; Proteins; Purkinje Cells - enzymology; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Glutamate - metabolism; Risk factors; RNA, Messenger - biosynthesis; Signal transduction; Signal Transduction - genetics; spinocerebellar ataxia 1; Spinocerebellar ataxias; Spinocerebellar Ataxias - etiology; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Symporters; Toxicity; Transgenic animals; Trinucleotide Repeat Expansion - genetics; TRPC Cation Channels; United States; United States > US; Texas
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/72101

The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions render the resulting proteins toxic to neurons, however, remains elusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occurred before detectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxicity.