The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7.
Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell-autonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.
Gatchel
Jennifer R
JR
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Watase
Kei
K
Thaller
Christina
C
Carson
James P
JP
Jafar-Nejad
Paymaan
P
Shaw
Chad
C
Zu
Tao
T
Orr
Harry T
HT
Zoghbi
Huda Y
HY
D000818:Animals; D000067696:Ataxin-1; D000067719:Ataxin-7; D000067528:Ataxins; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D013002:Somatomedins / Q000378:metabolism / Q000502:physiology*; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*
D000067696:Ataxin-1; D000067719:Ataxin-7; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; C000593831:Atxn7 protein, mouse; D018975:Insulin-Like Growth Factor Binding Protein 5; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D013002:Somatomedins