α-Synuclein strains cause distinct synucleinopathies after local and systemic administration.

Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.

Interrelations between technology for obtaining quantum dots and optoelectronic properties of semiconductors [Invited].

The mechanism and kinetics of growth of nanocrystals considered as quantum dots (those used as electronic blocks in optoelectronic devices) is investigated for the case when the growth and solving of them is controlled in parallel by diffusion (surface of volume) and by the rate of chemical reaction at surface of the nanocrystals (Wagner's mechanism of growth). It is shown that the total flow to and from the nanocrystal consists of two parts, viz. the diffusion and kinetic ones. Depending on the ratio x of the two parts of the total flow, the diffusion or Wagner's mechanism of growth predominates. For that, the size distribution function is determined for the specified x either by the curve corresponding to the generalized Chakraverty-Wagner distribution or from the generalized Lifshitz-Slyozov-Wagner distribution. Comparison of theoretically computed distributions with the experimentally obtained histograms is carried out.

Activation of ryanodine receptors influences the paired-pulse depression in cultured rat hippocampal neurons.

Role of intraterminal calcium stores in modulation of short-term plasticity of evoked inhibitory postsynaptic currents (IPSCs) was studied in synaptically connected cultured hippocampal neurons using patch-clamp technique in whole-cell configuration. Currents were induced by voltage stimulation which were applied externally to presynaptic fiber. Paired stimuli resulted in paired-pulse depression (n=18) or facilitation (n=7) of the second IPSC at interpulse intervals 150 and 500 ms. Calcium release from intracellular calcium stores was activated by local application of caffeine and ryanodine, ryanodine receptor agonists. One of the characteristics of short-term plasticity, the pair-pulsed ratio (ratio of amplitudes of second IPSC to first IPSC), decreased during addition of ryanodine (50 nM) from 0.79 +/- 0.02 to 0.71 +/- 0.04 (n=10). This change was observed only for cells that demonstrated pair-pulsed depression. We also studied the influence of caffeine and ryanodine on spontaneous currents. Attenuation of the mean amplitude to 0.71 +/- 0.06 and frequency to 0.42 +/- 0.08 (n=7) of spontaneous IPSCs was observed during application of caffeine (10 mM). Upon ryanodine application the mean amplitude did not change but frequency of spontaneous events decreased to 0.74 +/- 0.09 (n=12). The amplitudes of currents evoked by fast local application of gamma-aminobutyric acid (GABA 100 mM) were diminished in the presence of caffeine (10 mM) to 0.59 +/- 0.03 (n=5) and in the presence of ryanodine (50 nM) to 0.56 +/- 0.11 (n=7). Thus we conclude that endoplasmic reticular calcium stores are able to modulate synaptic transmission from both presynaptic (in assumption that short-term plasticity and spontaneous activity are believed to have presynaptic nature) and postsynaptic (since GABA-receptors are situated on postsynaptic cell) sides.