Sci. STKE, 20 May 2003
NEURODEGENERATION Bound to Aggregate
A common feature of some neurodegenerative diseases is the abnormal accumulation of proteins in neurons. In spinocerebellar ataxia type 1 (SCA1), an expanded polyglutamine tract in the protein ataxin-1 causes it to aggregate and become toxic in neurons, a process that appears dependent on the phosphorylation of a particular serine residue. Chen et al. have now discovered that phosphorylation of this serine in a toxic form of ataxin-1 [ataxin-1(82Q)] facilitates interaction with the regulatory signaling molecule 14-3-3. Overexpression of both 14-3-3 and ataxin-1(82Q) in transfected cells increased the stability of ataxin-1 and enhanced the formation of nuclear aggregates, where both proteins also localized. Expression of 14-3-3 in transgenic flies enhanced the toxic effects of ataxin-1(82Q) expression alone. The authors further determined that the serine-threonine kinase Akt phosphorylates ataxin-1 on the critical serine residue in vitro and in transfected cells. Although the function of 14-3-3 binding is not clear, it may increase ataxin-1 toxicity in cells by stabilizing a conformation that resists degradation.
H.-H. Chen, P. Fernandez-Funez, S. F. Acevedo, Y. C. Lam, M. D. Kaytor, M. H. Fernandez, A. Aiken, E. M. C. Skoulakis, H. T. Orr, J. Botas, H. Y. Zoghbi, Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113, 457-468 (2003). [Online Journal]
Citation: Bound to Aggregate. Sci. STKE 2003, TW194 (2003).
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