Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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.

Download full-text


Available from: Byoung-il Bae, Apr 28, 2015
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a ubiquitous enzyme that catalyzes the sixth step of glycolysis and thus, serves to break down glucose for energy production. Beyond the traditional aerobic metabolism of glucose, recent studies have highlighted additional roles played by GAPDH in non-metabolic processes, such as control of gene expression and redox post-translational modifications. Neuroproteomics have revealed high affinity interactions between GAPDH and Alzheimer's disease-associated proteins, including the β-amyloid, β-amyloid precursor protein and tau. This neuronal protein interaction may lead to impairment of the GAPDH glycolytic function in Alzheimer's disease and may be a forerunner of its participation in apoptosis. The present review examines the crucial implication of GAPDH in neurodegenerative processes and clarifies its role in apoptotic cell death.
    Pathologie Biologie 09/2014; 62(6). DOI:10.1016/j.patbio.2014.08.002 · 1.20 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human neurological disorders are associated with brain-enriched proteins in a major way. Homeostasis of such proteins is a critical event in brain functioning and development. Neuropathological studies of most common neurological disorders clearly show that accumulated, misfolded, mutant proteins are the preliminary causes for such disorders. Studies in the past few decades suggest that the ubiquitin proteasome system (UPS) network is a critical regulator of protein levels mammalian cells. To date, various proteins and substrates in UPS associated with neurological disorders have been identified, but molecular mechanisms and how they are associated with pathogenesis of neurological disorders are poorly understood. Understanding UPS network may set a new window to understand the pathogenesis of neurological disorders. Here we are reporting the current studies of UPS components in major neurological disorders, such as Parkinson's, Alzheimer's, autistic spectrum disorders, Huntington's, and multiple sclerosis.
    Animal cells and systems the official publication of the Zoological Society of Korea 01/2014; 18(03):383-387. DOI:10.1080/19768354.2013.855256 · 0.44 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: S-Nitrosylation is a redox-mediated posttranslational modification that regulates protein function via covalent reaction of nitric oxide (NO)-related species with a cysteine thiol group on the target protein. Under physiological conditions, S-nitrosylation can be an important modulator of signal transduction pathways, akin to phosphorylation. However, with aging or environmental toxins that generate excessive NO, aberrant S-nitrosylation reactions can occur and affect protein misfolding, mitochondrial fragmentation, synaptic function, apoptosis or autophagy. Here, we discuss how aberrantly S-nitrosylated proteins (SNO-proteins) play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Insight into the pathophysiological role of aberrant S-nitrosylation pathways will enhance our understanding of molecular mechanisms leading to neurodegenerative diseases and point to potential therapeutic interventions.
    Neuron 05/2013; 78(4):596-614. DOI:10.1016/j.neuron.2013.05.005 · 15.05 Impact Factor
Show more