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Identification of multiple QTLs linked to neuropathology in the engrailed-1 heterozygous mouse model of Parkinson's disease

Kurowska, Zuzanna LU ; Jewett, Michael LU ; Brattås, Per Ludvik LU ; Jimenez, Itzia LU ; Kenéz, Xuyian; Björklund, Tomas LU ; Nordström, Ulrika LU ; Brundin, Patrik LU and Swanberg, Maria LU (2016) In Scientific Reports 6.
Abstract

Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss... (More)

Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.

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author
organization
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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
6
publisher
Nature Publishing Group
external identifiers
  • scopus:84983757503
  • wos:000381747100001
ISSN
2045-2322
DOI
10.1038/srep31701
language
English
LU publication?
yes
id
151f8655-db2d-41df-b0d2-a0187b3c4876
date added to LUP
2016-12-02 13:45:03
date last changed
2017-08-06 05:14:23
@article{151f8655-db2d-41df-b0d2-a0187b3c4876,
  abstract     = {<p>Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.</p>},
  articleno    = {31701},
  author       = {Kurowska, Zuzanna and Jewett, Michael and Brattås, Per Ludvik and Jimenez, Itzia and Kenéz, Xuyian and Björklund, Tomas and Nordström, Ulrika and Brundin, Patrik and Swanberg, Maria},
  issn         = {2045-2322},
  language     = {eng},
  month        = {08},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Identification of multiple QTLs linked to neuropathology in the engrailed-1 heterozygous mouse model of Parkinson's disease},
  url          = {http://dx.doi.org/10.1038/srep31701},
  volume       = {6},
  year         = {2016},
}