Showing papers by "Valina L. Dawson published in 2013"
TL;DR: It is demonstrated that physiologic modification of parkin by hydrogen sulfide (H2S), termed sulfhydration, enhances its catalytic activity and implies that H2S donors may be therapeutic.
Abstract: Increases in S-nitrosylation and inactivation of the neuroprotective ubiquitin E3 ligase, parkin, in the brains of patients with Parkinson's disease are thought to be pathogenic and suggest a possible mechanism linking parkin to sporadic Parkinson's disease. Here we demonstrate that physiologic modification of parkin by hydrogen sulfide, termed sulfhydration, enhances its catalytic activity. Sulfhydration sites are identified by mass spectrometry analysis and are investigated by site-directed mutagenesis. Parkin sulfhydration is markedly depleted in the brains of patients with Parkinson's disease, suggesting that this loss may be pathologic. This implies that hydrogen sulfide donors may be therapeutic.
247 citations
TL;DR: Inhibition of PARP1 through gene deletion or drug inhibition reversed behavioral deficits and protected against dopamine neuron death in AIMP2 transgenic mice, indicating that brain-permeable PARP inhibitors could effectively delay or prevent disease progression in Parkinson's disease.
Abstract: In this study, the authors show that overexpression/accumulation of the parkin substrate AIMP2 induces an age-dependent degeneration of dopaminergic neurons and results in motor dysfunction. This effect is dependent on AIMP2-induced activation of PARP1, which, in turn, induces cell death via parthanatos.
182 citations
TL;DR: The role of well-characterized and newly discovered pADPr-binding modules in a diverse set of physiological functions is highlighted, highlighting the structural elements and the modular strategies developed by pAD Pr-binding proteins to exert a fine-tuned control of a variety of pathways.
144 citations
TL;DR: In this paper, Parkin is inactivated in sporadic PD via S-nitrosylation, oxidative and dopaminergic stress, and phosphorylation by the stress-activated kinase c-Abl, leading to the accumulation of AIMP2 and PARIS (ZNF746).
Abstract: Background: Parkinson's disease (PD) is a chronic progressive neurologic disorder, which affects approximately one million men and women in the US alone. PD represents a heterogeneous disorder with common clinical manifestations and, for the most part, common neuropathological findings. Objective: This short article reviews the role of the ubiquitin E3 ligase in sporadic PD. Methods: The role of parkin in sporadic PD was reviewed by querying PubMed. Results: Parkin is inactivated in sporadic PD via S-nitrosylation, oxidative and dopaminergic stress, and phosphorylation by the stress-activated kinase c-Abl, leading to the accumulation of AIMP2 and PARIS (ZNF746). Conclusion: Strategies aimed at maintaining parkin in a catalytically active state or interfering with the toxicity of AIMP2 and PARIS (ZNF746) offer new therapeutic opportunities.
74 citations
TL;DR: In neuronal cells, the presence of LRRK2G2019S pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation, and ultrastructural analysis of PC12-derived cells expressing mutant LRRk2G 2019S shows an altered intracellular vesicle distribution.
Abstract: The leucine-rich repeat kinase 2 (LRRK2) gene was found to play a role in the pathogenesis of both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large multi-domain protein that is expressed in different tissues. To date, the physiological and pathological functions of LRRK2 are not clearly defined. In this study we have explored the role of LRRK2 in controlling vesicle trafficking in different cellular or animal models and using various readouts. In neuronal cells, the presence of LRRK2G2019S pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation. Moreover, mutant LRRK2 affects the levels of dopamine receptor D1 on the membrane surface in neuronal cells or animal models. Ultrastructural analysis of PC12-derived cells expressing mutant LRRK2G2019S shows an altered intracellular vesicle distribution. Taken together, our results point to the key role of LRRK2 to control vesicle trafficking in neuronal cells.
65 citations
TL;DR: The current literature relating the interplay of miRNA and neuronal activity is reviewed and future directions for defining miRNA’s role in disease are provided.
Abstract: MicroRNAs (miRNAs) are small 19–23 nucleotide regulatory RNAs that function by modulating mRNA translation and/or turnover in a sequence-specific fashion. In the nervous system, miRNAs regulate the production of numerous proteins involved in synaptic transmission. In turn, neuronal activity can regulate the production and turnover of miRNA through a variety of mechanisms. In this way, miRNAs and neuronal activity are in a reciprocal homeostatic relationship that balances neuronal function. The miRNA function is critical in pathological states related to overexcitation such as epilepsy and stroke, suggesting miRNA’s potential as a therapeutic target. We review the current literature relating the interplay of miRNA and neuronal activity and provide future directions for defining miRNA’s role in disease.
54 citations
TL;DR: New potential molecular and synaptic striatal targets for the development of both symptomatic and neuroprotective strategies for PD are described and the interaction between adenosine A2A receptors and dopamine D2 receptors, on the role of a correct assembly of NMDA receptors, and on the sGC/cGMP/PKG pathway is focused on.
Abstract: The defining anatomical feature of Parkinson's disease (PD) is the degeneration of substantia nigra pars compacta (SNc) neurons, resulting in striatal dopamine (DA) deficiency and in the subsequent alteration of basal ganglia physiology. Treatments targeting the dopaminergic system alleviate PD symptoms but are not able to slow the neurodegenerative process that underlies PD progression. The nucleus striatum comprises a complex network of projecting neurons and interneurons that integrates different neural signals to modulate the activity of the basal ganglia circuitry. In this review we describe new potential molecular and synaptic striatal targets for the development of both symptomatic and neuroprotective strategies for PD. In particular, we focus on the interaction between adenosine A2A receptors and dopamine D2 receptors, on the role of a correct assembly of NMDA receptors, and on the sGC/cGMP/PKG pathway. Moreover, we also discuss the possibility to target the cell death program parthanatos and the kinase LRRK2 in order to develop new putative neuroprotective agents for PD acting on dopaminergic nigral neurons as well as on other basal ganglia structures.
33 citations
TL;DR: This work sought to identify small molecules that could be neuroprotective by targeting the parthanatos pathway, involving overactivation of PARP‐1.
Abstract: Background and Purpose
The current lack of disease-modifying therapeutics to manage neurological and neurodegenerative conditions justifies the development of more efficacious agents. One distinct pathway leading to neuronal death in these conditions and which represents a very promising and attractive therapeutic target is parthanatos, involving overactivation of PARP-1. We therefore sought to identify small molecules that could be neuroprotective by targeting the pathway.
Experimental Approach
Using HeLa cells, we developed and optimized an assay for high-throughput screening of about 5120 small molecules. Structure–activity relationship (SAR) study was carried out in HeLa and SH-SY5Y cells for molecules related to the initial active compound. The neuroprotective ability of each active compound was tested in cortical neuronal cultures.
Key Results
4'-Methoxyflavone (4MF) showed activity by preventing the decrease in cell viability of HeLa and SH-SY5Y cells caused by the DNA-alkylating agent, N-methyl-N‘-nitro-N-nitrosoguanidine (MNNG), which induces parthanatos. A similar compound from the SAR study, 3',4'-dimethoxyflavone (DMF), also showed significant activity. Both compounds reduced the synthesis and accumulation of poly (ADP-ribose) polymer and protected cortical neurones against cell death induced by NMDA.
Conclusions and Implications
Our data reveal additional neuroprotective members of the flavone class of flavonoids and show that methoxylation of the parent flavone structure at position 4′ confers parthanatos-inhibiting activity while additional methoxylation at position 3′, reported by others to improve metabolic stability, does not destroy the activity. These molecules may therefore serve as leads for the development of novel neurotherapeutics for the management of neurological and neurodegenerative conditions.
33 citations
TL;DR: It is demonstrated that there is a general somatic stem cell defect in Down syndrome (DS), and the deubiquitinase Usp16 gene located on HSA21 is a key epigenetic switch that regulates stem cell self-renewal and senescence in DS, and it is suggested that inhibiting or reducing HSA 21 may be beneficial in treating the sequelae of DS.
Abstract: Somatic stem cell activity is critical for tissue homeostasis. Defects in stem cells are thought to be involved in many diseases, including inherited disorders and aging (He et al , 2009). In a recent paper published in Nature , Adorno et al (2013) demonstrate that there is a general somatic stem cell defect in Down syndrome (DS), a congenital disorder with triplication of human chromosome 21 (HSA21; Roper and Reeves, 2006; Megarbane et al , 2009). They report that the deubiquitinase Usp16 gene located on HSA21 is a key epigenetic switch that regulates stem cell self‐renewal and senescence in DS, and suggest that inhibiting or reducing HSA21 may be beneficial in treating the sequelae of DS.
DS is the most common human chromosomal abnormality with triplication of all or part of HSA21 in humans. Individuals with DS uniformly exhibit varying degrees of developmental delays, mental retardation and premature ageing (Roper and Reeves, 2006; Megarbane et al , 2009). While the underlying mechanisms of these multifactorial alterations in different systems remain to be defined, one possibility is that the functional decline of adult stem cells may partially …
6 citations