L444P Gba1 mutation increases formation and spread of α-synuclein deposits in mice injected with mouse α-synuclein pre-formed fibrils

Parkinson disease is the most common neurodegenerative movement disorder, estimated to affect one in twenty-five individuals over the age of 80. Mutations in glucocerebrosidase 1 (GBA1) represent the most common genetic risk factor for Parkinson disease. The link between GBA1 mutations and α-synuclein accumulation, a hallmark of Parkinson disease, is not fully understood. Following our recent finding that Gba1 mutations lead to increased α-synuclein accumulation in mice, we have studied the effects of a single injection of mouse α-synuclein pre-formed fibrils into the striatum of Gba1 mice that carry a L444P knock-in mutation. We found significantly greater formation and spread of α-synuclein inclusions in Gba1-transgenic mice compared to wild-type controls. This indicates that the Gba1 L444P mutation accelerates α-synuclein pathology and spread

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

A calorimeter coupled with a magnetic spectrometer for the detection of primary cosmic antiprotons

A tracking calorimeter made of 3200 brass streamer tubes together with 3200 pick-up strips has been built to complement a magnetic spectrometer in order to detect cosmic antiprotons in space. The characteristics of such a calorimeter, the results of a preliminary test of a prototype as well as the properties of the whole apparatus are presented. The apparatus, designed to operate on a balloon at an altitude of about 40 km, can be considered as a second generation detector, capable in principle to solve the problem of the presence of low energy (≤1 Ge V/c) antiprotons in the cosmic rays which is still open because of the disagreement between the existent experimental data

Study of the granularity for a tracking calorimeter with optimal rejection of proton background in positron detection

In this paper we present a Monte Carlo study of a calorimeter response for an experiment to equip the magnetic facility of the USA space station. Main purpose in the design of such a calorimeter is the efficient discrimination between eloctromagnetic and hadronic showers. The estimated rejection power results to be better than 1·10−3 p/e+ for incident particles with energy between 10 GeV and 100GeV

Two years of flight of the Pamela experiment: results and perspectives

PAMELA is a satellite borne experiment designed to study with great accuracy cosmic rays of galactic, solar, and trapped nature in a wide energy range (protons: 80 MeV-700 GeV, electrons 50 MeV-400 GeV). Main objective is the study of the antimatter component: antiprotons (80 MeV-190 GeV), positrons (50 MeV-270 GeV) and search for antinuclei with a precision of the order of $10^{-8}$). The experiment, housed on board the Russian Resurs-DK1 satellite, was launched on June, $15^{th}$ 2006 in a $350\times 600 km$ orbit with an inclination of 70 degrees. In this work we describe the scientific objectives and the performance of PAMELA in its first two years of operation. Data on protons of trapped, secondary and galactic nature - as well as measurements of the December $13^{th}$ 2006 Solar Particle Event - are also provided.Comment: To appear on J. Phys. Soc. Jpn. as part of the proceedings of the International Workshop on Advances in Cosmic Ray Science March, 17-19, 2008 Waseda University, Shinjuku, Tokyo, Japa

The PAMELA Storage and Control Unit

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A new measurement of the antiproton-to-proton flux ratio up to 100 GeV in the cosmic radiation

A new measurement of the cosmic ray antiproton-to-proton flux ratio between 1 and 100 GeV is presented. The results were obtained with the PAMELA experiment, which was launched into low-earth orbit on-board the Resurs-DK1 satellite on June 15th 2006. During 500 days of data collection a total of about 1000 antiprotons have been identified, including 100 above an energy of 20 GeV. The high-energy results are a ten-fold improvement in statistics with respect to all previously published data. The data follow the trend expected from secondary production calculations and significantly constrain contributions from exotic sources, e.g. dark matter particle annihilations.Comment: 10 pages, 4 figures, 1 tabl

Influence of Drug-Carrier Polymers on Alpha-Synucleinopathies: A Neglected Aspect in New Therapies Development.

Current therapeutic strategies to treat neurodegenerative diseases, such as alpha-synucleinopathies, aim at enhancing the amount of drug reaching the brain. Methods proposed, such as intranasal administration, should be able to bypass the blood brain barrier (BBB) and even when directly intracerebrally injected they could require a carrier to enhance local release of drugs. We have investigated the effect of a model synthetic hydrogel to be used as drug carrier on the amount of alpha-synuclein aggregates in cells in culture. The results indicated that alpha-synuclein aggregation was affected by the synthetic polymer, suggesting the need for testing the effect of any used material on the pathological process before its application as drug carrier.Peer Reviewe

ASTROMAG: A Superconducting Particle Astrophysics Magnet Facility for the Space Station

This paper describes a superconducting magnet system which is the heart of a particle astrophysics facility to be mounted on a portion of the proposed NASA space station. This facility will complete the studies done by the electromagnetic observatories now under development and construction by NASA. The paper outlines the selection process of the type of magnet to be used to analyze the energy and momentum of charged particles from deep space. The ASTROMAG superconducting magnet must meet all the criteria for a shuttle launch and landing, and it must meet safety standards for use in or near a manned environment such as the space station. The magnet facility must have a particle gathering aperture of at least 1 square meter steradian and the facility should be capable of resolving heavy nuclei with a total energy of 10 Tev or more