Advanced

Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)

Springer, W; Puschmann, A. LU ; Fiesel, Fabienne C; Ando, Maya; Caulfield, Thomas R; Ogaki, K.; Heckman, M. G.; Hudec, Roman; James, Elle D and Opala, G., et al. (2016) 20th International Congress of Parkinson's Disease and Movement Disorders In Movement Disorders 31(Suppl. S2). p.282-282
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
dimer, endogenous compound, heterodimer, parkin, phosphotransferase, poison, protein, biochemistry, clinical evaluation, controlled study, dominant inheritance, effect size, family study, gene inactivation, gene mutation, genetic association, genetic risk, genetic susceptibility, heterozygote, human, imaging, meta analysis, mitochondrion, molecular dynamics, molecular model, Parkinson disease, pedigree analysis, phenotype, population based case control study, quality control, skin fibroblast, stress, structure activity relation, wild type
in
Movement Disorders
volume
31
issue
Suppl. S2
pages
1 pages
publisher
John Wiley & Sons
conference name
20th International Congress of Parkinson's Disease and Movement Disorders
ISSN
0885-3185
DOI
10.1002/mds.26688
language
English
LU publication?
yes
id
f167e4d5-95bb-4e32-aef0-c7f2b23b6eaa
date added to LUP
2017-07-04 16:03:03
date last changed
2017-10-04 03:00:12
@misc{f167e4d5-95bb-4e32-aef0-c7f2b23b6eaa,
  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.},
  author       = {Springer, W and Puschmann, A. and Fiesel, Fabienne C and Ando, Maya and Caulfield, Thomas R and Ogaki, K. and Heckman, M. G. and Hudec, Roman and James, Elle D and Opala, G. and Siuda, J and Boczarska-Jedynak, M. and Friedman, A. and Koziorowski, Dariusz and Aasly, Jan O. and Lynch, T. and Mellick, G. D. and Mohan, M. and Silburn, P. A. and Sanotsky, Y and Vilariño-Güell, C and Farrer, M J and Dawson, T M and Wszolek, Z K and Ross, O A},
  issn         = {0885-3185},
  keyword      = {dimer,endogenous compound,heterodimer,parkin,phosphotransferase,poison,protein,biochemistry,clinical evaluation,controlled study,dominant inheritance,effect size,family study,gene inactivation,gene mutation,genetic association,genetic risk,genetic susceptibility,heterozygote,human,imaging,meta analysis,mitochondrion,molecular dynamics,molecular model,Parkinson disease,pedigree analysis,phenotype,population based case control study,quality control,skin fibroblast,stress,structure activity relation,wild type},
  language     = {eng},
  note         = {Conference Abstract},
  number       = {Suppl. S2},
  pages        = {282--282},
  publisher    = {John Wiley & Sons},
  series       = {Movement Disorders},
  title        = {Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)},
  url          = {http://dx.doi.org/10.1002/mds.26688},
  volume       = {31},
  year         = {2016},
}