Redistribution of DAT/α-synuclein complexes visualized by “in situ” proximity ligation assay in transgenic mice modelling early Parkinson’s disease

Alpha-synuclein, the major component of Lewy bodies, is thought to play a central role in the onset of synaptic dysfunctions in Parkinson's disease (PD). In particular, α-synuclein may affect dopaminergic neuron function as it interacts with a key protein modulating dopamine (DA) content at the synapse: the DA transporter (DAT). Indeed, recent evidence from our "in vitro" studies showed that α-synuclein aggregation decreases the expression and membrane trafficking of the DAT as the DAT is retained into α-synuclein-immunopositive inclusions. This notwithstanding, "in vivo" studies on PD animal models investigating whether DAT distribution is altered by the pathological overexpression and aggregation of α-synuclein are missing. By using the proximity ligation assay, a technique which allows the "in situ" visualization of protein-protein interactions, we studied the occurrence of alterations in the distribution of DAT/α-synuclein complexes in the SYN120 transgenic mouse model, showing insoluble α-synuclein aggregates into dopaminergic neurons of the nigrostriatal system, reduced striatal DA levels and an altered distribution of synaptic proteins in the striatum. We found that DAT/α-synuclein complexes were markedly redistributed in the striatum and substantia nigra of SYN120 mice. These alterations were accompanied by a significant increase of DAT striatal levels in transgenic animals when compared to wild type littermates. Our data indicate that, in the early pathogenesis of PD, α-synuclein acts as a fine modulator of the dopaminergic synapse by regulating the subcellular distribution of key proteins such as the DAT

Lower grade gliomas: relationships between metabolic and structural imaging with grading and molecular factors

Background: Positron emission tomography (PET) is a valuable tool for the characterization of brain tumors in vivo. However, few studies have investigated the correlation between carbon-11-methionine (11C-METH) PET metrics and the clinical, radiological, histological, and molecular features of patients affected by lower grade gliomas (LGGs). The present observational study evaluated the relationships between 11C-METH PET metrics and structural magnetic resonance imaging (MRI) findings with the histomolecular biomarkers in patients with LGGs who were candidates for surgery. Methods: We enrolled 96 patients with pathologically proven LGG (51 men, 45 women; age 44.1 \ub1 13.7 years; 45 with grade II, 51 with grade III), who had been referred from March 2012 to January 2015 for tumor resection and had undergone preoperative 11C-METH PET. The semiquantitative metrics for 11C-METH PET included maximum standardized uptake value (SUVmax), SUV ratio to normal brain, and metabolic tumor burden (MTB). The PET semiquantitative metrics were analyzed and compared with the MRI features, histological diagnosis, isocitrate dehydrogenase-1/2 status, and 1p/19q codeletion. Results: Histological grade was associated with SUVmax (P = 0.002), SUV ratio (P = 0.011), and MTB (P = 0.001), with grade III lesions showing higher values. Among the nonenhancing lesions on MRI, SUVmax (P = 0.001), SUV ratio (P = 0.003) and MTB (P < 0.001) were significantly different statistically for grade II versus grade III. The MRI lesion volume correlated poorly with MTB (r 2 = 0.13). The SUVmax and SUV ratio were greater (P < 0.05) in isocitrate dehydrogenase-1/2 wild-type lesions, and the SUV ratio was associated with the presence of the 1p19q codeletion. Conclusions: The 11C-METH PET metrics correlated significantly with histological grade and the molecular profile. Semiquantitative PET metrics can improve the preoperative evaluation of LGGs and thus support clinical decision-making

Study of Leading Hadrons in Gluon and Quark Fragmentation

The study of quark jets in e+e- reactions at LEP has demonstrated that the hadronisation process is reproduced well by the Lund string model. However, our understanding of gluon fragmentation is less complete. In this study enriched quark and gluon jet samples of different purities are selected in three-jet events from hadronic decays of the Z collected by the DELPHI experiment in the LEP runs during 1994 and 1995. The leading systems of the two kinds of jets are defined by requiring a rapidity gap and their sum of charges is studied. An excess of leading systems with total charge zero is found for gluon jets in all cases, when compared to Monte Carlo Simulations with JETSET (with and without Bose-Einstein correlations included) and ARIADNE. The corresponding leading systems of quark jets do not exhibit such an excess. The influence of the gap size and of the gluon purity on the effect is studied and a concentration of the excess of neutral leading systems at low invariant masses (<~ 2 GeV/c^2) is observed, indicating that gluon jets might have an additional hitherto undetected fragmentation mode via a two-gluon system. This could be an indication of a possible production of gluonic states as predicted by QCD.Comment: 19 pages, 6 figures, Accepted by Phys. Lett.