A parkin szerepe a Parkinson-kórban

Parkin (Parkinson juvenile disease protein 2) is a ~52 kDa (426 amino acid) enzyme protein, encoded by PARK2 gene and located on the 6q chromosome. It plays an important role in the ubiquitin-proteasome system and acts as a regulator of protein breakdown. Parkin is located in the cytoplasma until a sustained depolarization occurs as a result of which it is translocated to the mitochondrial surface and induces the degradation of various membrane proteins which are candidates for mitophagia. Parkin is essential for cellular mitochondrial integrity. Parkin mutation leads to the accumulation of missfolded, aggregated proteins and degenerated mitochondria. The role of these changes in the pathomechanism of neurodegenerative diseases is well-known. It was a general belief for a long time that Parkinson's disease is without genetic component a sporadic disease. In 1997 a point mutation was, however, discovered in the alpha-synuclein gene, which caused dominantly inherited parkinsonism. At least 10 other genes were thereafter detected the mutation or deletion of which cause monogenic parkinsonism. Parkin mutation is responsible for about 50% of familial cases and for 10 to 20% of youth cases. According to the present views the improper regulation of protein aggregation and a dysfunction of the ubiquitin-proteasome system may be the common pathway of sporadic and hereditary Parkinson's disease. In the future it might have therapeutic value that parkin has versatile neuroprotective activity (against alpha-synuclein toxicity, proteasomal dysfunction, oxidative stress, kainite-induced and dopamine-mediated toxicity) as a result of which any reduction of parkin level or activity may cause damage in neuronal integrity

Az alpha-szinuklein szerepe Parkinson-kórban

alpha-synuclein, a small protein (140 amino acids) encoded by the SNCA gene is the best known isoform of the synuclein protein family. Though its physiological role is still not fully clarified, there is growing experimental evidence for a causal role of alpha-synuclein in the so-called conformational-neurodegenerative diseases. Conformational changes in the structure of the native soluble protein form insoluble neurotoxic aggregates and finally contribute to the formation of inclusion Lewy-bodies and Lewy-neurites. Neurodegeneration first hits the olfactory system, the peripheral autonomic nervous system, the enteric nervous system and the dorsal vagal motoneurons. The middle stage of the disease hits the dopaminergic neurons of the substantia nigra; and the neocortex is affected only in the late stage of the disease. This precise order of neurodegeneration is not always valid, but increases the likelihood that Lewy-bodies and neurodegenaration spread to intact areas in a prion-like way. Prions are infectious proteins which do not contain nucleic acids and cause diseases because they form toxic aggregates and filaments by misfolding in a beta-sheet-rich conformation. The misfolded protein behaves like a template inducing conformational change in the wild type proteins causing cross-reaction and leading to neurodegeneration. Later, the defective proteins may infect healthy nerve cells, thus neurodegeneration is extended. Growing experimental evidence shows that monomers and aggregates of alpha-synuclein are secreted via exocytosis from damaged nerve cells and taken up via endocytosis by healthy nerve cells furnishing evidence for the prion-like role of alpha-synuclein

Importance of a Nonlocal Description of Electron-Electron Interactions in Modeling the Dissociative Adsorption of H-2 on Cu(100)

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Formation of [Cu2O2](2+) and [Cu2O](2+) toward C-H Bond Activation in Cu-SSZ-13 and Cu-SSZ-39

Cu-exchanged small-pore zeolites (CHA and AEI) form methanol from methane (>95% selectivity) using a 3-step cyclic procedure (Wulfers et al. Chem. Commun. 2015, 51, 4447-4450) with methanol amounts higher than Cu-ZSM-5 and Cu-mordenite on a per gram and per Cu basis. Here, the CuxOy species formed on Cu-SSZ-13 and Cu-SSZ-39 following O-2 or He activation at w450 degrees C are identified as trans-mu-1,2-peroxo dicopper(II) ([Cu2O2](2+)) and mono-(mu-oxo) dicopper(II) ([Cu2O](2+)) using synchrotron X-ray diffraction, in situ UV vis, and Raman spectroscopy and theory. [Cu2O](2+). and [Cu2O](2+) formed on Cu-SSZ-13 showed ligand-to-metal charge transfer (LMCT) energies between 22,200 and 35,000 cm(-1), Cu-O vibrations at 360, 510, 580, and 617 cm-(1) and an 0-0 vibration at 837 cm(-1). The vibrations at 360, 510, 580, and 837 cm(-1) are assigned to the trans-mu-1,2-peroxo dicopper(II) species, whereas the Cu-O vibration at 617 cm(-1) (Delta O-18 = 24 cm(-1)) is assigned to a stretching vibration of a thermodynamically favored mono-(mu-oxo) dicopper(II) with a Cu-O-Cu angle of 95 degrees. On the basis of the intensity loss of the broad LMCT band between 22,200 and 35,000 cm(-1) and Raman intensity loss at 571 cm(-1) upon reaction, both the trans-mu-1,2-peroxo dicopper(II) and mono-(mu-oxo) dicopper(II) species are suggested to take part in methane activation at 200 degrees C with the trans-mu-1,2-peroxo dicopper(II) core playing a dominant role. A relationship between the [Cu2Oy](2+) concentration and Cu(II) at the eight-membered ring is observed and related to the concentration of [CuOH]+ suggested as an intermediate in [Cu2Oy](2+) formation

Bulk Liquid Water at Ambient Temperature and Pressure from MP2 Theory

MP2 provides a good description of hydrogen bonding in water clusters and includes long-range dispersion interactions without the need to introduce empirical elements in the description of the interatomic potential. To assess its performance for bulk liquid water under ambient conditions, an isobaric-isothermal (NpT) Monte Carlo simulation at the second-order Moller-Plesset perturbation theory level (MP2) has been performed. The obtained value of the water density is excellent (1.02 g/mL), and the calculated radial distribution functions are in fair agreement with experimental data. The MP2 results are compared to a few density functional approximations, including semilocal functionals, hybrid functionals, and functionals including empirical dispersion corrections. These results demonstrate the feasibility of directly sampling the potential energy surface of condensed-phase systems using correlated wave function theory, and their quality paves the way for further applications

Quantum Chemical Free Energies: Structure Optimization and Vibrational Frequencies in Normal Modes

A computational protocol is presented that uses normal mode coordinates for structure optimization and for obtaining harmonic frequencies by numerical differentiation. It reduces numerical accuracy problems encountered when density functional theory with plane wave basis sets is applied to systems with flat potential energy surfaces. The approach is applied to calculate Gibbs free energies for adsorption of methane, ethane, and propane on the Brønsted acidic sites of zeolite H-CHA. The values obtained (273.15 K, 0.1 MPa,), -0.25, -5.95, and -16.76 kJ/mol, respectively, follow the trend of the experimental values, which is not the case for results obtained with the standard approach (Cartesian optimization, frequencies from Cartesian distortions). Anharmonicity effects have been approximately taken into account by solving one-dimensional Schrödinger equations along each normal mode. This leads to a systematic increase of the Gibbs free energy of adsorption of 4.5, 5.0, and 3.1 kJ/mol for methane, ethane, and propane, respectively, making adsorption at a given pressure and temperature less likely. This is due to an increase of low vibrational frequencies associated with hindered translations and rotations of the adsorbed molecules and the floppy modes of the zeolite framework. © 2013 American Chemical Society