The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Jennifer R. Gatchel, Kei Watase, Christina Thaller, James P. Carson, Paymaan Jafar-Nejad, Chad Shaw, Tao Zu, Harry T. Orr, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1291-1296
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number4
DOIs
StatePublished - Jan 29 2008

Keywords

  • Cerebellum
  • Granule neuron
  • Neurodegeneration
  • Polyglutamine
  • Purkinje cell

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