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- Springer, W, et al.
(author)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Conference paper (peer-reviewed)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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| 3. |
- Hennig, A., et al.
(author)
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Mixed-symmetry octupole and hexadecapole excitations in N=52 isotones
- 2015
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In: EPJ Web of Conferences. - : EDP Sciences. - 2101-6275 .- 2100-014X. - 9782759817948 ; 93
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Conference paper (peer-reviewed)abstract
- In addition to the well-established quadrupole mixed-symmetry states, octupole and hexadecapole excitations with mixed-symmetry character have been recently proposed for the N = 52 isotones 92Zr and 94Mo. We performed two inelastic proton-scattering experiments to study this kind of excitations in the heaviest stable N = 52 isotone 96Ru. From the combined experimental data of both experiments absolute transition strengths were extracted.
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| 4. |
- Hennig, A., et al.
(author)
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Study of mixed-symmetry excitations in Ru-96 via inelastic proton-scattering
- 2015
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In: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 580:1
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Conference paper (peer-reviewed)abstract
- Mixed-symmetry states of octupole (L = 3) and hexadecapole (L = 4) character have been recently proposed in the N = 52 isotones Zr-92 and Mo-94, based on strong M1 transitions to the lowest-lying 3(-) and 4(+) states, respectively. In order to investigate similar excitations in the heaviest stable N = 52 isotone Ru-96, two inelastic proton-scattering experiments have been performed at the Wright Nuclear Structure Laboratory (WNSL), Yale University, USA and the Institute for Nuclear Physics, University of Cologne, Germany. From the combined data of both experiments, absolute E-1, M-1, and E2 transition strengths were extracted, allowing for the identification of candidates for MS octupole and hexadecapole states. The structure of the low-lying 4(+) states is investigated by means of sdg-IBM-2 calculations.
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