Identifying polyglutamine protein species in situ that best predict neurodegeneration

Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Nature Chemical Biology (Impact Factor: 13). 12/2011; 7(12):925-34. DOI: 10.1038/nchembio.694
Source: PubMed


Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

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    • ") and, in a mechanistic parallel with the pathogenic mechanisms proposed for " classical " amyloids, many studies suggested that the insoluble inclusions played a protective role, sequestering toxic, and misfolded protein conformers (Arrasate et al., 2004; Rub et al., 2006; Miller et al., 2010). Indeed, soluble intermediates in the aggregation pathway such as misfolded β-sheet rich polyQ protein monomers and oligomers have latter been identified and proposed to represent the major toxic species (Kayed et al., 2003; Gales et al., 2005; Nagai et al., 2007; Miller et al., 2011). Also, in OPMD, the primary toxic species are proposed to be the soluble variants of the expanded polyA-repeat protein PABPN1 (Messaed et al., 2007). "
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