Novel variant Pro143Ala in HTRA2 contributes to Parkinson’s disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria

Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson’s disease (PD). We assessed the presence of HTRA2 mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire HTRA2 coding region was sequenced in 113 early-onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C > G (Pro143Ala) and c.906 +3 G > A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late-onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5–2.8, P = 0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD

Asymmetrization Effects on Structures and Populations of the Ground State of Dipolar Donor-Acceptor-Substituted Molecular Organic NLO Materials

Asymmetric donor-acceptor-substituted π-conjugated systems with low dipole moments and structural components that favor parallel alignment of neighboring molecules are potential molecular organic materials with nonlinear optical properties for which near prefect dipole parallel alignment is possible. The asymmetrical 4-methoxysubstituted acetophenone azines with the substituents fluorine (1), chlorine (2), bromine (3), cyano (4), and nitro (5) in the 4\u27-position have been studied in this context, and for 2 and 3 the dipole parallel alignment has indeed been accomplished in crystals of the pure material. In the present study, the effects of asymmetrization on the structure and the electronic structures of the ground states of 1-5 have been explored at the RHF/6-31G* level. The properties of the optimized structures of the azines 1-5, a comparative analysis of asymmetrical and symmetrical azines, and natural population analyses, all show no significant evidence for conjugation over the azine bridge. The concept of azine spacers as conjugation stoppers is useful and the dipole moments of asymmetrical azines are relatively small. The analysis suggests that the charge transfer between the donor and acceptor contributes to the dipole moment much less than is generally assumed

Electronic Structure Analysis of the Nonlinear Optical Materials 4-Nitropyridine N-Oxide (NPO) and 3-Methyl-4-nitropyridine N-Oxide (POM)

The molecules 4-nitropyridine N-oxide (NPO) and 3-methyl-4-nitropyridine N-oxide (POM) and the models nitromethane and N-methylnitrone were studied with ab initio electronic structure theory at the RHF level and with the inclusion of electron correlation using perturbation and density functional theories. At the highest level, MP2(full)/6-311G**//MP2(full)/6-31G*, the dipole moments μ(NPO) = 0.97 and μ(POM) = 0.89 D were obtained. Methyl substitution leads to only a small reduction of Δμ \u3c 0.1 D and the computed dipole moments are in excellent agreement with recent experimental data. The dipole vector of NPO points away from the nitro group (-pole) toward the NO group (+pole) and the dipole vector in POM is rotated such as to point toward the Me-substituted half. The electric quadrupole moments of NPO and POM indicate quadrupolarity {- + -} along all axes and the &vbar;Qzz&vbar; values are particularly large. Natural Population analysis reveals the common electronic motif for NPO and POM consisting in an electron-deficient hydrocarbon midsection embedded between electron-rich functional groups. The dipole direction in the pyridine N-oxides thus does not reflect contributions by the quinoid resonance form (electron density shifts from the NO to the NO2 group) to the ground-state electronic structure. The directions of the molecular dipole moments of the pyridine N-oxides are the simple result of vector addition of the two inward pointing dipoles that are associated with the functional groups and caused by electronegativity differences. In contrast to X-ray electron density studies, the electronic consequences of H/Me replacement are found to be localized. Approximate molecular dipole moments based on point charge models (PCM) are compared to the correct dipole moments. The analysis of the PCM-derived dipole moments shows that a discussion of solid-state effects on the molecular dipole moments of NPO and POM must be postponed until the true dipole moments in the crystal have been more rigorously established

A Theoretical Analysis of 2,3 Sigmatropic Shifts in Allylic Sulfilimines and Sulfoximines

Ab initio calculations at the level MP4(SDTQ,full)/6-31G*//MP2(full)/6-31G* + AVZPE(MP2(full)/6-31G*) support the experimental observation that allylic sulfoximines do not undergo 2,3 sigmatropic shifts. This process is hindered by a high kinetic barrier although the reaction is strongly exothermic

β,β-dichlorovinyldiazonium or Dichloro(diazomethyl)carbenium Ion? Crystal Structure and Electron Density Distribution of β,β- Dichlorovinyldiazonium Hexachloroantimonate

The crystal structure of β,β-dichlorovinyldiazonium hexachloroantimonate, 2·SbCl6, and the topological electron density analysis of 2 provide compelling evidence for the importance of chlorine-stabilized carbenium ion resonance forms for the stabilization of vinyldiazonium ions by β-substitution

Conjugation in Azines. Stereochemical Analysis of Benzoylformate Azines in the Solid State, in Solution, and in the Gas Phase

The stereochemistry of benzoylformate azines 3 was studied in the solid state (X-rays, IR), in solution (1H-, 13C-, and 15N-NMR), and in the gas phase (ab initio theory). Benzoylformate azines are excellent systems to study phenyl conjugation because the ester substituent is electron-withdrawing and in a conformation that impedes π backdonation thereby causing the azine-C to be highly electron-deficient and an excellent potential acceptor for π-donation. The X-ray structure of ethyl benzoylformate azine (3a) is reported and compared to the crystallographic record. Azines 3 assume the N-N s-trans conformation and the Z, Z configuration. The phenyl groups are in the molecular plane of the Ci-symmetric azine while the carboxyl groups lie in planes that are nearly perpendicular. The solid-state structures are compared to optimized ab initio structures of geometrical isomers of 3. RHF/6-31G*//RHF/3-21G energies indicate the ordering Z, Z \u3e E, Z \u3e E, E for the thermodynamic preferences and suggest that 3 prefers the same stereochemistry in the gas phase as in the solid state. Phenyl conjugation is shown to be of little importance. 1H-, 13C-, and 15N-NMR spectroscopic analyses indicate the presence of one isomer in solution consistent with the stereochemical preferences found in the solid state and in vacuum. Infrared (calcd and exptl) and Raman (calcd) spectra show features characteristic of azines, but only the latter might be useful in stereochemical analyses. The stereochemical preferences differ markedly from those of the azines of esters, and an explanation is proposed

Origin of the Stabilization of Vinyldiazonium Ions by β-Substitution; First Crystal Structure of an Aliphatic Diazonium Ion: β,β-Diethoxyethene-diazonium Hexachloroantimonate

The considerable contributions of the O-stabilized mesomeric resonance structures III and IV probably account for the extraordinary stability of the cation of the title compound and related systems. This is apparent from comparisons of the bond lengths and angles of the first experimentally determined structure with the results of ab initio studies. The title compound is prepared by alkylation of diazoacetate with triethyloxonium hexachloroantimonate

Comparative Analysis of Crystal Structures of E,E-Configured Para-Substituted Acetophenone Azines with Halogen, Oxygen, Nitrogen and Carbon Functional Groups

A comparative analysis is presented of the solid state structures of fifteen E,E-configured para-substituted acetophenone azines with halogen [-F (1a), -Cl (1b), -Br (1c)], oxygen [-OMe (2, 5 and 6), -OH (3), -OCOEt (4)], nitrogen [-NMe2 (7), -NH2 (8), -NHCOMe (9), -NO2 (10)] and carbon [-Me (11), -CO2Et (12), -CN (13)] functional groups. The X-ray crystal structures of 2, 7-10 and 12 were determined and are reported. The data allow us systematically to examine the structural effects of the nature of the para-substituent in a series of closely related azines and to assess and distinguish between intrinsic electronic and steric effects and consequences of crystal packing. Stereoelectronic effects of the para-substituents are discussed in terms of contributions of various resonance forms and structural parameters are identified that may serve as indicators of their importance. Analyses are presented of conformational properties and of crucial bond lengths of the azines 1-13. The molecules also are analysed as para-disubstituted benzenes X-C6H4-Az and compared with X-C6H4-Z systems qualitatively to rank the electron-withdrawing ability of the Az group

Dipole Moments of the Nonlinear Optical Materials NPO and POM

Solution-phase measurements and ab initio quantum-mechanical calculations (MP2/6-311G**//MP2/6-31G*) of the dipole moments of 4-nitropyridine N-oxide (µexptl = 0.83 ± 0.04 D, µcalc = 0.97 D) and 3-methyl-4-nitropyridine N-oxide (µexptl = 0.69 ± 0.05 D, µcalc = 0.89 D) show that the electronic effects of methyl substitution are localized and much smaller (Δµ \u3c 0.2 D) than had previously been thought