Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Parkinson’s disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs

Variations of the spectral index of dust emissivity from Hi-GAL observations of the Galactic plane

Original article can be found at: http://www.aanda.org/ Copyright The European Southern ObservatoryContext. Variations in the dust emissivity are critical for gas mass determinations derived from far-infrared observations, but also for separating dust foreground emission from the Cosmic Microwave Background (CMB). Hi-GAL observations allow us for the first time to study the dust emissivity variations in the inner regions of the Galactic plane at resolution below 1°. Aims. We present maps of the emissivity spectral index derived from the combined Herschel PACS 160 μm, SPIRE 250 μm, 350 μm, and 500 μm data, and the IRIS 100 μm data, and we analyze the spatial variations of the spectral index as a function of dust temperature and wavelength in the two science demonstration phase Hi-GAL fields, centered at l = 30° and l = 59°. Methods. Applying two different methods, we determine both dust temperature and emissivity spectral index between 100 and 500 μm, at an angular resolution (θ) of 4'. Results. Combining both fields, the results show variations of the emissivity spectral index in the range 1.8–2.6 for temperatures between 14 and 23 K. The median values of the spectral index are similar in both fields, i.e. 2.3 in the range 100–500 μm, while the median dust temperatures are equal to 19.1 K and 16.0 K in the l = 30° and l = 59° field, respectively. Statistically, we do not see any significant deviations in the spectra from a power law emissivity between 100 and 500 μm. We confirm the existence of an inverse correlation between the emissivity spectral index and dust temperature, found in previous analyses.Peer reviewe

Source extraction and photometry for the far-infrared and sub-millimeter continuum in the presence of complex backgrounds

(Abridged) We present a new method for detecting and measuring compact sources in conditions of intense, and highly variable, fore/background. While all most commonly used packages carry out the source detection over the signal image, our proposed method builds from the measured image a "curvature" image by double-differentiation in four different directions. In this way point-like as well as resolved, yet relatively compact, objects are easily revealed while the slower varying fore/background is greatly diminished. Candidate sources are then identified by looking for pixels where the curvature exceeds, in absolute terms, a given threshold; the methodology easily allows us to pinpoint breakpoints in the source brightness profile and then derive reliable guesses for the sources extent. Identified peaks are fit with 2D elliptical Gaussians plus an underlying planar inclined plateau, with mild constraints on size and orientation. Mutually contaminating sources are fit with multiple Gaussians simultaneously using flexible constraints. We ran our method on simulated large-scale fields with 1000 sources of different peak flux overlaid on a realistic realization of diffuse background. We find detection rates in excess of 90% for sources with peak fluxes above the 3-sigma signal noise limit; for about 80% of the sources the recovered peak fluxes are within 30% of their input values.Comment: Accepted on A&

Direct Estimate of Cirrus Noise in Herschel Hi-GAL Images

In Herschel images of the Galactic plane and many star forming regions, a major factor limiting our ability to extract faint compact sources is cirrus confusion noise, operationally defined as the "statistical error to be expected in photometric measurements due to confusion in a background of fluctuating surface brightness". The histogram of the flux densities of extracted sources shows a distinctive faint-end cutoff below which the catalog suffers from incompleteness and the flux densities become unreliable. This empirical cutoff should be closely related to the estimated cirrus noise and we show that this is the case. We compute the cirrus noise directly, both on Herschel images from which the bright sources have been removed and on simulated images of cirrus with statistically similar fluctuations. We connect these direct estimates with those from power spectrum analysis, which has been used extensively to predict the cirrus noise and provides insight into how it depends on various statistical properties and photometric operational parameters. We report multi-wavelength power spectra of diffuse Galactic dust emission from Hi-GAL observations at 70 to 500 microns within Galactic plane fields at l= 30 degrees and l= 59 degrees. We find that the exponent of the power spectrum is about -3. At 250 microns, the amplitude of the power spectrum increases roughly as the square of the median brightness of the map and so the expected cirrus noise scales linearly with the median brightness. Generally, the confusion noise will be a worse problem at longer wavelengths, because of the combination of lower angular resolution and the rising power spectrum of cirrus toward lower spatial frequencies, but the photometric signal to noise will also depend on the relative spectral energy distribution of the source compared to the cirrus.Comment: 4 pages (in journal), 3 figures, Astronomy and Astrophysics, accepted for publication 13 May 201

Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates

Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard ADHD medication, methylphenidate (MPH), a monoamine transporter inhibitor whose efficacy appears related with the stimulation of brain-derived neurotrophic factor (BDNF). Interestingly, we previously showed that MPH can bind Syn III, which can regulate neuronal development. These observations suggest that Syn III polymorphism may impinge on ADHD onset and response to therapy by affecting BDNF-dependent dopaminergic neuron development. Here, by studying zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and human induced pluripotent stem cells (iPSCs)-derived neurons subjected to Syn III RNA interference, we found that Syn III governs the earliest stages of dopaminergic neurons development and that this function is conserved in vertebrates. We also observed that in mammals Syn III exerts this function acting upstream of brain-derived neurotrophic factor (BDNF)- and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. Collectively, these findings own significant implications for deciphering the biological basis of ADHD

The pre-ZAMS nature of Mol160/IRAS23385+6053 confirmed by Spitzer

Determining the timeline for the formation of massive YSOs requires the identification and characterisation of all the phases that a massive forming YSO undergoes. It is of particular interest to verify the observability of the phase in which the object is rapidly accreting while not yet igniting the fusion of hydrogen that marks the arrival on the ZAMS. One of the candidate prototypical objects for this phase is Mol160/IRAS23385+6053, which previous studies suggest it could be in a pre-Hot Core stage. We further investigate this issue by means of Spitzer imaging and spectroscopy in the 5-70 micron range. The dense core of Mol160/IRAS23385+6053, which up to now had only been detected at submm and mm wavelenghts has been revealed for the first time at 24 and 70 micron by Spitzer. The complete 24 micron -3.4 mm continuum cannot be fitted with a standard model of a Zero-Age Main-Sequence (ZAMS) star embedded in an envelope. A simple greybody fit yields a mass of 220 solar masses. The luminosity is slightly in excess of 3000 solar luminosities, which is a factor of 5 less than previous estimates when only IRAS fluxes were available between 20 and 100 micron. The source is under-luminous by the same factor with respect to UCHII regions or Hot-Cores of similar circumstellar mass, and simple models show that this is compatible with an earlier evolutionary stage. Spectroscopy between 5 and 40 microns revelas typical PDR/PIR conditions, where the required UV illumination may be provided by other sources revealed at 24 microns in the same region, and which can be plausibly modeled as moderately embedded intermediate-mass ZAMS stars. Our results strengthen the suggestion that the central core in Mol160/IRAS23385+6053 is a massive YSO actively accreting from its circumstellar envelope and which did not yet begin hydrogen fusion.Comment: Accepted by A&

Transient transfection of porcine granulosa cells after 3D culture in barium alginate capsules

Three-dimensional culture systems in barium alginate capsules can be employed to maintain primary granulosa cells in an undifferentiated state for almost 6 days. This is due to a self-organization of cells in a pseudofollicular structure. The transfection of primary granulosa cells is a necessary condition when employing these culture systems for several purposes, for example as an in vitro toxicity test or the development of oocytes or zygotes. In this work, the feasibility of two transient transfection techniques (liposome-mediated and electroporation) was assessed in primary porcine granulosa cells after a 6-day culture in an artificial extracellular matrix (barium alginate membrane). Human recombinant green fluorescent protein was chosen as a molecular readout, and protein expression was assessed after 48 hours from transfection. Liposome-mediated transfection gave low transfection levels, with increasing yields from 2 to 12 microgDNA/ml of medium; the maximum percentage (85.7%) was reached at 12 microgDNA/ml of medium. Electroporation-mediated transfection yields were higher: the best results (81.7% of transfected cells) were achieved with two 50V pulses and 12 microg/ml DNA. The application of a single or double pulse (50V) at 4 mgDNA/ml gave negligible results. These results indicate that primary granulosa cell cultured in barium alginate capsules can be transfected by electroporation with high transfection yields

What are we losing? Are the personality traits of Italian autochthonous cows different from those of cosmopolitan breeds?

Objective: This study assessed personality traits in five cattle breeds (Bos taurus), two cosmopolitan (Holstein Friesian and Brown Swiss) and three endangered Italian autochthonous (Varzese, Rendena, and Modenese). Our aim was to provide an evaluation of the personality dimensions obtained by our questionnaire in order to compare some Italian autochthonous breeds with the cosmopolitan one. Our choice fell upon the comparison of the Varzese, the Modenese, the Rendena, the Brown Swiss, and the Holstein Friesian because the genetic selection at the base of the typical attitudes has induced different characteristics, and as a consequence, detectable differences in personality can be expected between the populations. Materials and methods: A personality questionnaire was completed by milkers/owners for each subject involved in this study. The milking staff involved in the study have been working with cows for over 20 years; they have experience with numerous breeds, and therefore, can be considered expert evaluators since they certainly have an appreciation of the full range of cow behavior. Results: The milkers\u2019 assessments analysis found breed differences in dairy cattle, showing that certain personality traits are more marked in certain breeds in terms of curiosity, friendliness to milkers, and responses to unknown people. Conclusion: This pilot survey shows the usefulness of questionnaires in cattle personality studies, highlighting some peculiarity of the endangered breeds

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy

Comparison between Cloprostenol-induced and Spontaneous Oestrus Fertility in Dairy Cows

A short calving to conception interval is of main importance to achieve high economic efficiency in dairy cow industry. In order to reduce this interval, several hormonal treatments have been put on the market, in which cloprostenol, a synthetic analogue of prostaglandin F2 (PGF2). The aim of this study was to compare fertility of cloprostenol-induced oestrus to that of spontaneous oestrus in dairy cows. In a group of 525 cows, 280 (treated group) were administered 0.5 mg cloprostenol i.m. after transrectal corpus luteum (CL) detection, and inseminated at detected oestrus during the following week. The other 245 cows (control group) were inseminated during spontaneous oestrus. Whey progesterone concentrations were checked at treatment and at insemination in order to remove from the study cows whose P4 levels indicate a non-functional CL, or a lack of luteolysis respectively. Moreover, cows that were not inseminated due to genital problems were also excluded from this study. Conception (59% vs 54.5%) and calving rates (93.7% vs 93%) were not significantly different between the two groups