The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Multidimensional Proteomics Analysis of Amniotic Fluid to Provide Insight into the Mechanisms of Idiopathic Preterm Birth

Though recent advancement in proteomics has provided a novel perspective on several distinct pathogenetic mechanisms leading to preterm birth (inflammation, bleeding), the etiology of most preterm births still remains elusive. We conducted a multidimensional proteomic analysis of the amniotic fluid to identify pathways related to preterm birth in the absence of inflammation or bleeding.A proteomic fingerprint was generated from fresh amniotic fluid using surface-enhanced laser desorbtion ionization time of flight (SELDI-TOF) mass spectrometry in a total of 286 consecutive samples retrieved from women who presented with signs or symptoms of preterm labor or preterm premature rupture of the membranes. Inflammation and/or bleeding proteomic patterns were detected in 32% (92/286) of the SELDI tracings. In the remaining tracings, a hierarchical algorithm was applied based on descriptors quantifying similarity/dissimilarity among proteomic fingerprints. This allowed identification of a novel profile (Q-profile) based on the presence of 5 SELDI peaks in the 10-12.5 kDa mass area. Women displaying the Q-profile (mean+/-SD, gestational age: 25+/-4 weeks, n = 40) were more likely to deliver preterm despite expectant management in the context of intact membranes and normal amniotic fluid clinical results. Utilizing identification-centered proteomics techniques (fluorescence two-dimensional differential gel electrophoresis, robotic tryptic digestion and mass spectrometry) coupled with Protein ANalysis THrough Evolutionary Relationships (PANTHER) ontological classifications, we determined that in amniotic fluids with Q-profile the differentially expressed proteins are primarily involved in non-inflammatory biological processes such as protein metabolism, signal transduction and transport.Proteomic profiling of amniotic fluid coupled with non-hierarchical bioinformatics algorithms identified a subgroup of patients at risk for preterm birth in the absence of intra-amniotic inflammation or bleeding, suggesting a novel pathogenetic pathway leading to preterm birth. The altered proteins may offer opportunities for therapeutical intervention and future drug development to prevent prematurity

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.In the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.Taken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE

The conserved dileucine- and tyrosine-based motifs in MLV and MPMV envelope glycoproteins are both important to regulate a common Env intracellular trafficking

BACKGROUND: Retrovirus particles emerge from the assembly of two structural protein components, Gag that is translated as a soluble protein in the cytoplasm of the host cells, and Env, a type I transmembrane protein. Because both components are translated in different intracellular compartments, elucidating the mechanisms of retrovirus assembly thus requires the study of their intracellular trafficking. RESULTS: We used a CD25 (Tac) chimera-based approach to study the trafficking of Moloney murine leukemia virus and Mason-Pfizer monkey virus Env proteins. We found that the cytoplasmic tails (CTs) of both Env conserved two major signals that control a complex intracellular trafficking. A dileucine-based motif controls the sorting of the chimeras from the trans-Golgi network (TGN) toward endosomal compartments. Env proteins then follow a retrograde transport to the TGN due to the action of a tyrosine-based motif. Mutation of either motif induces the mis-localization of the chimeric proteins and both motifs are found to mediate interactions of the viral CTs with clathrin adaptors. CONCLUSION: This data reveals the unexpected complexity of the intracellular trafficking of retrovirus Env proteins that cycle between the TGN and endosomes. Given that Gag proteins hijack endosomal host proteins, our work suggests that the endosomal pathway may be used by retroviruses to ensure proper encountering of viral structural Gag and Env proteins in cells, an essential step of virus assembly

Virus Movements on the Plasma Membrane Support Infection and Transmission between Cells

How viruses are transmitted across the mucosal epithelia of the respiratory, digestive, or excretory tracts, and how they spread from cell to cell and cause systemic infections, is incompletely understood. Recent advances from single virus tracking experiments have revealed conserved patterns of virus movements on the plasma membrane, including diffusive motions, drifting motions depending on retrograde flow of actin filaments or actin tail formation by polymerization, and confinement to submicrometer areas. Here, we discuss how viruses take advantage of cellular mechanisms that normally drive the movements of proteins and lipids on the cell surface. A concept emerges where short periods of fast diffusive motions allow viruses to rapidly move over several micrometers. Coupling to actin flow supports directional transport of virus particles during entry and cell-cell transmission, and local confinement coincides with either nonproductive stalling or infectious endocytic uptake. These conserved features of virus–host interactions upstream of infectious entry offer new perspectives for anti-viral interference

Retroviral matrix and lipids, the intimate interaction

Retroviruses are enveloped viruses that assemble on the inner leaflet of cellular membranes. Improving biophysical techniques has recently unveiled many molecular aspects of the interaction between the retroviral structural protein Gag and the cellular membrane lipids. This interaction is driven by the N-terminal matrix domain of the protein, which probably undergoes important structural modifications during this process, and could induce membrane lipid distribution changes as well. This review aims at describing the molecular events occurring during MA-membrane interaction, and pointing out their consequences in terms of viral assembly. The striking conservation of the matrix membrane binding mode among retroviruses indicates that this particular step is most probably a relevant target for antiviral research