Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson’s Disease

• Published in: Scientific reports Vol. 6; no. 1; p. 31701
• Main Authors: Kurowska, Zuzanna, Jewett, Michael, Brattås, Per Ludvik, Jimenez-Ferrer, Itzia, Kenéz, Xuyian, Björklund, Tomas, Nordström, Ulrika, Brundin, Patrik, Swanberg, Maria
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.08.2016; Nature Publishing Group
• Subjects: 631/208/207; 631/378/1689; Animal models; Animals; Axons; Basal ganglia; Basic Medicine; Central nervous system diseases; Disease Models, Animal; Dopamine; Dopamine receptors; Dopaminergic Neurons - metabolism; Female; Gene mapping; Genetic Predisposition to Disease - genetics; Genomes; Genotype & phenotype; Heterozygosity; Heterozygote; Homeodomain Proteins - genetics; Humanities and Social Sciences; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mesencephalon; Mice, Inbred C57BL; Mice, Knockout; Motor task performance; Movement disorders; multidisciplinary; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neuropathology; Neurosciences; Neurovetenskaper; Parkinson Disease - genetics; Parkinson's disease; Quantitative trait loci; Quantitative Trait Loci - genetics; Science; Science (multidisciplinary); Substantia nigra; Substantia Nigra - metabolism; Substantia Nigra - pathology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep31701

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.