Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH

Johns Hopkins University, Baltimore, Maryland, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2006; 103(9):3405-9. DOI: 10.1073/pnas.0511316103
Source: PubMed


The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.

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Available from: Byoung-il Bae, Apr 28, 2015
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    • "However, recent experimental evidence suggest that beyond glycolytic functions, GAPDH is in reality a multifunctional protein that has been reported to: bind nucleic acids [21] [22], regulate gene expression/transcription [23], possess kinase/phosphotransferase activity [24], facilitate vesicular transport [25], and bind integral membrane ion pumps associated with cell Ca 2+ release [26], as well as interact with a number of small key molecules, including ribozymes [27], glutathione (GSH) [28], p53 [29], and nitric oxide (NO) [30] [31] [32] [33]. Moreover, GAPDH also interacts and form complexes with neurodegenerative disease-related proteins, like huntingtin [33] [34], b-amyloid and the b-amyloid precursor protein (AbPP) [35] [36] [37] [38]. "
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    • "It has been reported that Siah1 is involved in the nuclear translocation and cytotoxicity of mouse HTT in association with GADPH. Siah1-GADPH complex together with various polyQ proteins alters the location of mouse HTT in the brain cells (Bae et al. 2006). TRAF6 (Tumor necrosis factor associated factor 6) is an E3 ligase which has been suggested as a candidate for pathogen of PD and AD. "
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    • "S-Nitrosylation enhances the binding of GAPDH to Siah1, an E3 ubiquitin ligase, and the SNO-GAPDH/Siah1 protein complex is translocated to the nucleus, where it mediates apoptosis (Figure 5; Hara et al., 2005). The GAPDH-Siah1 pathway also participates in nuclear translocation of mutant huntingtin protein (mtHtt), mediating, at least in part, neurotoxicity in HD (Bae et al., 2006). In the nucleus, GAPDH stimulates the activity of p300/CBP and activates downstream targets including Figure 5. Schematic Representation of SNO-GAPDH Pathways Formation of SNO-GAPDH can trigger multiple signaling pathways leading to neurodegeneration. "
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