title: Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease.
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 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.
authors.affiliation: Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 17, 221 84 Lund, Sweden.|Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Renovo Neural Inc., 10000 Cedar Avenue, Cleveland 44106, OH, USA.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Kurowska
authors.affiliation: Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Jewett
authors.affiliation: Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Per Ludvik
authors.initials: PL
authors.lastname: Brattås
authors.affiliation: Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Itzia
authors.initials: I
authors.lastname: Jimenez-Ferrer
authors.affiliation: Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Xuyian
authors.initials: X
authors.lastname: Kenéz
authors.affiliation: Molecular Neuromodulation Unit, Lund University, Biomedical Center A10, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Björklund
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Byggnad 6M NUS, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Nordström
authors.affiliation: Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.affiliation: Neurodegeneration and Inflammation Genetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Swanberg
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics; D000069338:Neuropathology; D010300:Parkinson Disease / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
chemical_list: C080330:En1 protein, mouse; D018398:Homeodomain Proteins