The influence of media violence on youth

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83429/1/2003.Anderson_etal.InfluenceofMediaViolenceonYouth.PsychologicalScienceinthePublicInterest.pd

Caspase inhibition, a potential therapeutic strategy in neurological diseases

Caspases are intracellular proteases that participate in apoptotic pathways in mammalian cells, including neurons. Here we review evidence that caspase inhibition, through pharmacological or molecular means, rnay inhibit neuronal cell death in a number of in vitro and in vivo models of neurological disease. It has recently become clear that, at least in most cell culture models, caspase inhibition offers only transient protection, and that a caspase-independent death eventually occurs. This rnay be due to irreversible caspase-independent alterations at the leve1 of the mitochondria. Despite concerns that targeting caspases alone rnay prove insufficient to truly reverse the effects of various death stimuli, in vivo studies indicate that caspase inhibition promotes survival and functional outcome in a variety of neurological disease models. In addition, studies of human post-mortem material suggest that caspases are activated in certain human neurological diseases. Caspase inhibition rnay therefore provide a novel strategy for the treatment of such disorders. Caspas'es, through the generation of toxic fragments of critica1 protein substrates, rnay also be involved in earlier steps of neuronal dysfunction, such as protein aggregation in Huntington's and Alzheimer's disease, and therefore caspase inhibition rnay be of additional value in the treatment of these particular disorders

Ubiquitinated inclusions and neuronal cell death

Summary. Ubiquitinated inclusions and selective neuronal cell death are considered the pathological hallmarks of Parkinson’s disease and other neurodegenerative diseases. Recent genetic, pathological and biochemical evidence suggests that dysfunction of ubiquitin-dependent protein degradation by the proteasome might be a contributing, if not initiating factor in the pathogenesis of these diseases. In neuronal cell culture models inhibition of the proteasome leads to cell death and formation of fibrillar ubiquitin and a- synuclein-positive inclusions, thus modeling some aspects of Lewy body diseases. The processes of inclusion formation and neuronal cell death share some common mechanisms, but can also be dissociated at a certain level

Targeted disruption of neuronal 19S proteasome subunits induces the formation of ubiquitinated inclusions in the absence of cell death

Proteasome-mediated proteolysis is a major protein degradation mechanism in cells and its dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, each with the common features of neuronal death and formation of ubiquitinated inclusions found within neurites, the cell body, or nucleus. Previous models of proteasome dysfunction have employed pharmacological inhibition of the catalytic subunits of the 20S proteasome core, or the genetic manipulation of specific subunits resulting in altered proteasome assembly. In this study, we report the use of dominant negative subunits of the 19S regulatory proteasome complex that mediate the recognition of ubiquitinated substrates as well as the removal of the poly-ubiquitin chain. Interestingly, while each mutant subunit-induced inclusion formation, like that seen with pharmacological inhibition of the 20S proteasome, none was able to induce apoptotic death, or trigger activation of macroautophagy, in either dopaminergic cell lines or primary cortical neurons. This finding highlights the dissociation between the mechanisms of neuronal inclusion formation and the induction of cell death, and represents a novel cellular model for Lewy body-like inclusion formation in neurons. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry

Activation of FADD-Dependent neuronal death pathways as a predictor of pathogenicity for LRRK2 mutations

Background Despite the plethora of sequence variants in LRRK2, only a few clearly segregate with PD. Even within this group of pathogenic mutations, the phenotypic profile can differ widely. Objective We examined multiple properties of LRRK2 behavior in cellular models over-expressing three sequence variants described in Greek PD patients in comparison to several known pathogenic and non-pathogenic LRRK2 mutations, to determine if specific phenotypes associated with pathogenic LRRK2 can be observed in other less-common sequence variants for which pathogenicity is unclear based on clinical and/or genetic data alone. Methods The oligomerization, activity, phosphorylation, and interaction with FADD was assessed in HEK293T cells over-expressing LRRK2; while the induction of neuronal death was determined by quantifying apoptotic nuclei in primary neurons transiently expressing LRRK2. Results One LRRK2 variant, A211V, exhibited a modest increase in kinase activity, whereas only the pathogenic mutants G2019S and I2020T displayed significantly altered auto-phosphorylation. We observed an induction of detergent-insoluble high molecular weight structures upon expression of pathogenic LRRK2 mutants, but not the other LRRK2 variants. In contrast, each of the variants tested induced apoptotic death of cultured neurons similar to pathogenic LRRK2 in a FADD-dependent manner. © 2016 Melachroinou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD. © 2017, National Academy of Sciences. All rights reserved