The roles of the others remain to be explored. The second molecular feature of the red module

is the presence of six 14-3-3 family proteins (Ywhab, Ywhae, Ywhag, Wnt inhibitor Ywhah, Ywhaq, Ywhaz), with Ywhae as a top hub protein (Figure 6A). Impressively, “14-3-3-Mediated Signaling” in the Red Module is the most significantly enriched IPA Canonical Pathway for all modules in the fl-Htt interactome network (Table S13). The 14-3-3 pathway has been implicated in the pathogenesis of a variety of neurodegenerative disorders (Chen et al., 2003), and four 14-3-3 members have been shown to physically or genetically interact with Htt N-terminal fragments (Kaltenbach et al., 2007 and Omi et al., 2008) (Table S3). Since 14-3-3 proteins are phosphoserine/phosphothreonine

binding proteins (Morrison, 2009), and Htt phosphorylation at several serine residues has been shown to modify HD pathogenesis (Humbert et al., 2002, Gu et al., 2009 and Thompson et al., 2009), it could be a promising direction to investigate whether 14-3-3 proteins in the red module could directly interact with relevant phospho-Htt species to affect the disease process. The third molecular pathway enriched in the red module is “Intracellular Protein Transport” (Dynactin, Dynein, Vcp, and Ran) consistent with the convergent evidence supporting the role of Htt function in the microtubule-based transport process (Caviston and Holzbaur, 2009) and the disruption selleckchem of such function in HD (Gauthier et al., 2004). Although the red module appears to be enriched with proteins from divergent molecular processes, several lines of evidence suggest these proteins indeed have close biological connectivity. First, 26 out of the 61 red module proteins are included in the same IPA network, which is constructed based on the archived IPA Knowledge Base derived from published studies. This network has the highest IPA network score among all of the networks constructed

from Htt interactome modules (Table S13), suggesting that the proteins in red module already have a close functional link based on existing knowledge. Second, the red Endonuclease module has a marked enrichment for proteins implicated in other neurological and genetic disorders. Using another IPA core analysis (IPA Function), the red module has dramatically higher enrichment for proteins in the categories of Neurological Disorders and Genetic Disorders compared to the other modules (Figures S3A and S3B), which cannot be accounted for by enrichment of the HD Signaling Pathway alone (Figure 4C). Furthermore, 16 red module proteins (Figures S3C and S3D) are mutated in neurological disorders ranging from Frontotemporal dementia (Vcp) to Parkinson’s disease (Vps35).