Biomedicine

A Stabilizing Partner

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Science  06 Jun 2003:
Vol. 300, Issue 5625, pp. 1479
DOI: 10.1126/science.300.5625.1479a

A number of human neurodegenerative diseases are caused by genetically encoded expansions of polyglutamine tracts in the disease-causing proteins. These mutant proteins form intraneuronal aggregates that may arise from aberrant stabilization of the proteins, but the mechanism by which this occurs and how the stabilization is linked to neuronal death remain unclear.

Studying spinocerebellar ataxia type 1 (SCA1), an inherited neurodegenerative disease caused by polyglutamine expansion in ataxin-1, Chen et al. found that ataxin-1 interacts with and is stabilized by 14-3-3 proteins, a family of phosphopeptide-binding proteins previously shown to regulate many forms of cellular signaling. The binding of 14-3-3 promoted the accumulation of ataxin-1 in neurons and required phosphorylation of ataxin-1 at serine-776 by Akt, a protein kinase implicated in neuronal survival pathways. Both 14-3-3 and Akt modified ataxin-1 neurotoxicity in a fly model of SCA1. That serine-776 plays a critical role in the pathogenesis of SCA1 was also documented by Emamian et al. in a related mouse study. Further dissection of these molecular interactions may help identify drug targets for these devastating disorders.—PAK

Cell 113, 457 (2003); Neuron 38, 375 (2003).

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