Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1.
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.
Lin
X
X
Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Antalffy
B
B
Kang
D
D
Orr
H T
HT
Zoghbi
H Y
HY
D027322:Amino Acid Transport System X-AG; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001921:Brain / Q000201:enzymology; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D005786:Gene Expression Regulation; D050491:Glutamate Plasma Membrane Transport Proteins; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000201:enzymology*; D009687:Nuclear Proteins; D009928:Organ Specificity; D010455:Peptides / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011496:Protein Methyltransferases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D011689:Purkinje Cells / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D027981:Symporters; D050052:TRPC Cation Channels; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000514:alpha 1-Antichymotrypsin / Q000378:metabolism
C000593749:ATXN1 protein, human; D027322:Amino Acid Transport System X-AG; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D015220:Calcium Channels; D050491:Glutamate Plasma Membrane Transport Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D017470:Receptors, Glutamate; D027981:Symporters; D050052:TRPC Cation Channels; D000514:alpha 1-Antichymotrypsin; C096351:transient receptor potential cation channel, subfamily C, member 1; C097188:polyglutamine; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D000252:Calcium-Transporting ATPases