Publications (145) View all
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Article: S-Nitrosylation of Drp1 Mediates Mutant Huntingtin-Induced Mitochondrial Fragmentation and Neuronal Injury in Huntington's Disease.
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ABSTRACT: Aims: Dynamin related protein1 (Drp1) is a large GTPase that mediates mitochondrial fission. We recently reported in Alzheimer's disease (AD) that S-nitrosylation of Drp1 (forming SNO-Drp1) results in GTPase hyperactivity and mitochondrial fragmentation, thus impairing bioenergetics and inducing synaptic damage and neuronal loss. Here, since aberrant mitochondrial dynamics are also key features of Huntington's disease (HD), we investigated whether formation of SNO-Drp1 contributes to the pathogenesis of HD in cell-based and animal models. Results: We found that expression of mutant huntingtin (mutHTT) protein in primary cultured neurons triggers significant production of nitric oxide (NO). Consistent with this result, increased levels of SNO-Drp1 were found in the striatum of a transgenic mouse model of HD as well as in human postmortem brains from HD patients. Using specific fluorescence markers, we found that formation of SNO-Drp1 induced excessive mitochondrial fragmentation followed by loss of dendritic spines, signifying synaptic damage. These neurotoxic events were significantly abrogated after transfection with non-nitrosylatable mutant Drp1(C644A), or by the blocking of NO production using an NO synthase inhibitor. These findings suggest that SNO-Drp1 is a key mediator of mutHTT toxicity and thus may represent a novel drug target for HD. Innovation and Conclusion: Our findings indicate that aberrant S-nitrosylation of Drp1 is a prominent pathological feature of neurodegenerative diseases such as AD and HD. Moreover, the SNO-Drp1 signaling pathway links mutHTT neurotoxicity to a malfunction in mitochondrial dynamics, resulting in neuronal synaptic damage in HD.Antioxidants & Redox Signaling 05/2013; · 8.20 Impact Factor -
Article: S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke.
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ABSTRACT: Overproduction of nitric oxide (NO) can cause neuronal damage, contributing to the pathogenesis of several neurodegenerative diseases and stroke (i.e., focal cerebral ischemia). NO can mediate neurotoxic effects at least in part via protein S-nitrosylation, a reaction that covalently attaches NO to a cysteine thiol (or thiolate anion) to form an S-nitrosothiol. Recently, the tyrosine phosphatase Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) and its downstream pathways have emerged as important mediators of cell survival. Here we report that in neurons and brain tissue NO can S-nitrosylate SHP-2 at its active site cysteine, forming S-nitrosylated SHP-2 (SNO-SHP-2). We found that NMDA exposure in vitro and transient focal cerebral ischemia in vivo resulted in increased levels of SNO-SHP-2. S-Nitrosylation of SHP-2 inhibited its phosphatase activity, blocking downstream activation of the neuroprotective physiological ERK1/2 pathway, thus increasing susceptibility to NMDA receptor-mediated excitotoxicity. These findings suggest that formation of SNO-SHP-2 represents a key chemical reaction contributing to excitotoxic damage in stroke and potentially other neurological disorders.Proceedings of the National Academy of Sciences 02/2013; · 9.68 Impact Factor -
Article: High-Frequency Hippocampal Oscillations Activated by Optogenetic Stimulation of Transplanted Human ESC-Derived Neurons.
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ABSTRACT: After transplantation, individual stem cell-derived neurons can functionally integrate into the host CNS; however, evidence that neurons derived from transplanted human embryonic stem cells (hESCs) can drive endogenous neuronal network activity in CNS tissue is still lacking. Here, using multielectrode array recordings, we report activation of high-frequency oscillations in the β and γ ranges (10-100 Hz) in the host hippocampal network via targeted optogenetic stimulation of transplanted hESC-derived neurons.Journal of Neuroscience 11/2012; 32(45):15837-42. · 7.11 Impact Factor -
Article: Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration.
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ABSTRACT: PURPOSE. The herb rosemary has been reported to have anti-oxidant and anti-inflammatory activity. We have previously shown that carnosic acid (CA), present in rosemary extract, crosses the blood-brain-barrier to exert neuroprotective effects by upregulating endogenous anti-oxidant enzymes via the Nrf2 transcriptional pathway. Here, we investigate the anti-oxidant and neuroprotective activity of CA in retinal cell lines exposed to oxidative stress and in a rat model of light-induced retinal degeneration (LIRD). METHODS. Retinal-derived cell lines ARPE-19 and 661W treated with hydrogen peroxide were used as in vitro models for testing the protective activity of CA. For in vivo testing, dark adapted rats were given intraperitoneal injections of CA prior to exposure to white light to assess protection of the photoreceptor cells. Retinal damage was assessed by measuring outer nuclear layer thickness and ERG. RESULTS. In vitro, CA significantly protected retinal-derived cell lines (ARPE-19 and 661W) against H2O2-induced toxicity. CA induced anti-oxidant, phase 2 enzymes and reduced formation of hyperoxidized peroxiredoxin (Prx)2. Similarly, we found that CA protected retinas in vivo from LIRD, producing significant improvement in outer nuclear layer (ONL) thickness and electroretinogram (ERG) activity. CONCLUSIONS. These findings suggest that CA may potentially have clinical application to diseases affecting the outer retina, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP), in which oxidative stress is thought to contribute to disease progression.Investigative ophthalmology & visual science 10/2012; · 3.43 Impact Factor -
Article: S-nitrosylation of Cdk5: Potential implications in amyloid-β-related neurotoxicity in Alzheimer disease.
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ABSTRACT: Aberrant activation of Cdk5 has been implicated in the process of neurodegenerative diseases such as Alzheimer's disease (AD). We recently reported that S-nitrosylation of Cdk5 (forming SNO-Cdk5) at specific cysteine residues results in excessive activation of Cdk5, contributing to mitochondrial dysfunction, synaptic damage, and neuronal cell death in models of AD. Furthermore, SNO-Cdk5 acts as a nascent S-nitrosylase, transnitrosylating the mitochondrial fission protein Drp1 and enhancing excessive mitochondrial fission in dendritic spines. However, a molecular mechanism that leads to the formation of SNO-Cdk5 in neuronal cells remained obscure. Here, we demonstrate that neuronal nitric oxide synthase (NOS1) interacts with Cdk5 and that the close proximity of the two proteins facilitates the formation of SNO-Cdk5. Interestingly, as a negative feedback mechanism, Cdk5 phosphorylates and suppresses NOS1 activity. Thus, together with our previous report, these findings delineate an S-nitrosylation pathway wherein Cdk5/NOS1 interaction enhances SNO-Cdk5 formation, mediating mitochondrial dysfunction and synaptic loss during the etiology of AD.Prion 09/2012; 6(4):364-70. · 2.85 Impact Factor
