Browsing by Author "Huang, Xudong"

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    The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen
    (Springer Nature, 2011-03) Rogers, Jack T.; Mikkilineni, Sohan; Castelvetri, Ippolita Cantuti; Smith, Deborah H.; Huang, Xudong; Bandyopadhyay, Sanghamitra; Cahill, Catherine M.; Maccecchini, Maria L.; Lahiri, Debomoy K.; Greig, Nigel H.; Psychiatry, School of Medicine
    Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo.
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    Manganese causes neurotoxic iron accumulation via translational repression of Amyloid Precursor Protein (APP) and H-Ferritin
    (Wiley, 2018-12-27) Venkataramani, Vivek; Doeppner, Thorsten R.; Willkommen, Desiree; Cahill, Catherine M.; Xin, Yongjuan; Ye, Guilin; Liu, Yanyan; Southon, Adam; Aron, Allegra; Au‐Yeung, Ho Yu; Huang, Xudong; Lahiri, Debomoy K.; Wang, Fudi; Bush, Ashley I.; Wulf, Gerald G.; Ströbel, Philipp; Michalke, Bernhard; Rogers, Jack T.; Psychiatry, School of Medicine
    For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD‐like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose‐ and time‐dependently blocks the protein translation of amyloid precursor protein (APP) and heavy‐chain Ferritin (H‐Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H‐Ferritin are post‐transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5′‐untranslated regions (5′‐UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5′‐UTR‐activity of APP and H‐Ferritin, presumably via increased iron responsive proteins‐iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+‐specific probes (RhoNox‐1 and IP‐1) and ion chromatography inductively coupled plasma mass spectrometry (IC‐ICP‐MS), we show that loss of the protective axis of APP and H‐Ferritin resulted in unchecked accumulation of redox‐active ferrous iron (Fe2+) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn‐induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn‐mediated suppression of APP and H‐Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn‐induced neurotoxicity is partly attributable to the translational inhibition of APP and H‐Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress.
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    N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and Parkinson's disease
    (Bentham Science Publishers, 2012-07) Olivares, David; Deshpande, Varun K.; Shi, Ying; Lahiri, Debomoy K.; Greig, Nigel H.; Rogers, Jack T.; Huang, Xudong; Department of Psychiatry, IU School of Medicine
    Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer's disease (AD) treatment within the U.S. and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson's disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine-as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine's therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine's tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy.
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    Novel drug targets based on metallobiology of Alzheimer's disease
    (Taylor & Francis, 2010-11) Bandyopadhyay, Sanghamitra; Huang, Xudong; Lahiri, Debomoy K.; Rogers, Jack T.; Psychiatry, School of Medicine
    IMPORTANCE OF THE FIELD: Increased localization of Zn, Fe, Cu and Al within the senile plaques (SP) exacerbates amyloid beta (Aβ)-mediated oxidative damage, and acts as catalyst for Aβ aggregation in Alzheimer's disease (AD). Thus, disruption of aberrant metal-peptide interactions via chelation therapy holds considerable promise as a rational therapeutic strategy against Alzheimer's amyloid pathogenesis. AREAS COVERED IN THIS REVIEW: The complexities of metal-induced genesis of SP are reviewed. The recent advances in the molecular mechanism of action of metal chelating agents are discussed with critical assessment of their potential to become drugs. WHAT THE READER WILL GAIN: Taking into consideration the interaction of metals with the metal-responsive elements on the Alzheimer's amyloid precursor protein (APP), readers will gain understanding of several points to bear in mind when developing a screening campaign for AD-therapeutics. TAKE HOME MESSAGE: A functional iron-responsive element (IRE) RNA stem loop in the 5' untranslated region (UTR) of the APP transcript regulates neural APP translation. Desferrioxamine, clioquinol, tetrathiolmolybdate, dimercaptopropanol, VK-28, and natural antioxidants, such as curcumin and ginko biloba need critical evaluation as AD therapeutics. There is a necessity for novel screens (related to metallobiology) to identify therapeutics effective in AD.