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.
Highlights
Genetic analyses have identified several gene mutations in familial forms of PD, such as missense mutations in α-Syn and leucine rich repeat kinase 2 (LRRK2)[5]
We confirm a 24% loss of dopaminergic neurons (DNs) in 17 week-old SwissOF1-En1+/−mice compared to wild-type mean number of cells 7346 and 9642, respectively, p < 0.0001 (Fig. 1a–c)
The mean number of DNs in C57Bl/6 wt (6890) and N4 mice was in accordance with previous reports for C57Bl/636, but as much as 29% lower than in SwissOF1 wt mice (9642, p < 0.0001, Fig. 1a, b, d)
Summary
Genetic analyses have identified several gene mutations in familial forms of PD, such as missense mutations in α-Syn and leucine rich repeat kinase 2 (LRRK2)[5]. Recent studies in mice have identified En1 and En2 as survival and regulatory factors for adult DNs19, and En2 has been shown able to compensate for loss of En1 activity, partly restoring the function and integrity of DNs19–22. Striatal DA signaling, autophagy and axonal integrity were recently found to be impaired in Lmx1a/b genetic PD models[29]. This further strengthens the relevance of En1 mice as a model to study PD degenerative processes. In PD models, susceptibility to MPTP- and paraquat-induced degeneration of DNs in SNpc has been mapped to three distinct QTLs in N2 back-crosses between toxin-sensitive C57BL/6J and toxin-resistant Swiss-Webster mice[34,35]. The goal of this study was to map dopaminergic cell susceptibility loci by linkage analysis in the En1 heterozygous mouse model of PD
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