TY - CHAP
T1 - Phosphorylation of Ataxin-1
T2 - A Link Between Basic Research and Clinical Application in Spinocerebellar Ataxia Type 1
AU - Carlson, Kerri M.
AU - Orr, Harry T.
N1 - Publisher Copyright:
© 2006 Elsevier Inc. All rights reserved.
PY - 2006/7/11
Y1 - 2006/7/11
N2 - Spinocerebellar Ataxia type 1 (SCAl) is an autosomal dominant neurodegenerative disease caused by an expanded polyglutamine tract in ataxin-1. Phosphorylation of ataxin-1 at S776 is an important mediator of ataxin-1 turnover and SCAl pathogenesis. Mice expressing a SCA1 transgene are behaviorally indistinguishable from wild-type mice. Pathologically, these mice develop a very mild SCAl phenotype late in life. On a molecular level, S776 has been shown to mediate the interaction between ataxin-1 and 14-3-3. 14-3-3 binding to ataxin-1 stabilizes the ataxin-1 protein. A cell-based assay can also be used to identify two signaling pathways important for regulating S776 phosphorylation. One pathway appears to work in a calcium-dependent manner to phosphorylate both mutant and wild-type ataxin-1. The second pathway is mutant specific and involves PI3K/AKT signaling. The discovery of S776 phosphorylation is an important regulator of ataxin-1 turnover, as well as the identification of two signaling pathways involved in this regulation opened up a new area to explore for therapeutic development in SCAl.
AB - Spinocerebellar Ataxia type 1 (SCAl) is an autosomal dominant neurodegenerative disease caused by an expanded polyglutamine tract in ataxin-1. Phosphorylation of ataxin-1 at S776 is an important mediator of ataxin-1 turnover and SCAl pathogenesis. Mice expressing a SCA1 transgene are behaviorally indistinguishable from wild-type mice. Pathologically, these mice develop a very mild SCAl phenotype late in life. On a molecular level, S776 has been shown to mediate the interaction between ataxin-1 and 14-3-3. 14-3-3 binding to ataxin-1 stabilizes the ataxin-1 protein. A cell-based assay can also be used to identify two signaling pathways important for regulating S776 phosphorylation. One pathway appears to work in a calcium-dependent manner to phosphorylate both mutant and wild-type ataxin-1. The second pathway is mutant specific and involves PI3K/AKT signaling. The discovery of S776 phosphorylation is an important regulator of ataxin-1 turnover, as well as the identification of two signaling pathways involved in this regulation opened up a new area to explore for therapeutic development in SCAl.
UR - http://www.scopus.com/inward/record.url?scp=84882467252&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84882467252&partnerID=8YFLogxK
U2 - 10.1016/B978-012369462-1/50023-5
DO - 10.1016/B978-012369462-1/50023-5
M3 - Chapter
AN - SCOPUS:84882467252
SN - 9780123694621
SP - 339
EP - 349
BT - Genetic Instabilities and Neurological Diseases
PB - Elsevier
ER -