. A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell. 2006 May 19;125(4):801-14. PubMed.

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  1. It takes a lot of courage and conviction to undertake large-scale yeast two-hybrid (Y2H) studies, because they result in large harvests of data, with a lot of chaff mixed in with the wheat. Lim et al. have performed a large-scale Y2H study to specifically identify the interaction partners of proteins directly and indirectly implicated in neurodegeneration of cerebellar Purkinje cells, using a number of approaches to minimize the high false negative and false positive rates typically associated with Y2H-based investigations. These approaches included parallel Y2H screens using both cDNA and “ORFeome” libraries and complementary bait/prey and prey/bait screens. In addition, a subset of the predicted interactions was supported by an independent cotransfection/coimmunoprecipitation assay.

    The most important result of this study is that a subset of the 23 proteins directly implicated in Purkinje cell degeneration can be grouped into a tight interaction network, implying that mutations in these (seemingly unrelated) proteins induce neurodegeneration by impinging on the same biological process. The validity of the predicted interaction network was supported by two interesting observations: 1) some of the interacting proteins had been previously identified as genetic modifiers of degeneration in related animal models (a completely independent method using biologically relevant assays), and 2) one of the identified interacting proteins, puratrophin-1, was subsequently implicated in a novel autosomal dominant cerebellar ataxia.

    Although important things have been learned by this extensive study, it is unclear if the general approach will be applicable to other neurodegenerative diseases, such as Alzheimer’s. In part, this is due to the relatively few proteins with a strongly supported direct role in AD, thus limiting the extent to which a network could reasonably be developed. It is also possible that the set of disease-associated proteins used in this study might be particularly well suited for this approach. Specifically, I note that in the well-supported interaction subnetwork centered on ATXN1 (Figure 6 in this paper), 4/5 target disease proteins contain glutamine repeats (and hence are susceptible to CAG repeat expansion mutations). It is unknown why these disease-associated proteins contain glutamine repeats, but it is reasonable to assume that these (unexpanded) repeat regions have a biological function, perhaps as an interaction domain allowing modulation of the function of their host protein by other proteins. If this is true, these types of proteins may more readily fall into a sensible interaction network than other sets of disease-associated proteins.

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