Nigral Transcriptomic Profiles in Engrailed-1 Hemizygous Mouse Models of Parkinson’s Disease Reveal Upregulation of Oxidative Phosphorylation-Related Genes Associated with Resistance to Dopaminergic Neurodegeneration

Engrailed 1 (EN1) is a conserved transcription factor essential for programming, survival, and maintenance of midbrain dopaminergic neurons. En1 -hemizygosity ( En1 +/-) leads to a spontaneous Parkinson’s disease-like (PD-like) progressive nigrostriatal degeneration as well as motor impairment and depressive-like behavior in SwissOF1 (OF1 -En1 +/-) mice. This phenotype is absent in C57Bl/6j (C57 -En1 +/-) mice. Here we studied PD-like phenotypes and early transcriptome profiles in OF1 wild-type (WT) and OF1- En1 +/- male mice and compare to that of C57 WT and C57- En1 +/- male mice. To detect transcriptional changes prior to dopaminergic cell loss, we performed RNA-seq of 1-week old mice substantia nigra pars compacta (SNpc). Histology and stereology were used to assess dopaminergic nigrostriatal pathology in 4 and 16 weeks old mice. OF1- En1 +/- mice showed an increase (±79%) in dopaminergic striatal axonal swellings from 4 to 16 weeks and a loss (±23%) of dopaminergic neurons in the SNpc at 16 weeks compared to OF1 WT. Axonal swellings were also present in C57- En1 +/- mice but did not increase over time. 52 differentially expressed genes (DEGs) were observed between the C57-WT and the C57- En1 +/- mice, while 198 DEGs were observed in the OF1 strain. Enrichment analysis revealed that the neuroprotective phenotype of C57- En1 +/- mice was associated with an upregulation of oxidative phosphorylation-related genes compared to both C57 WT and to OF1- En1 +/- mice. These results highlight the importance of considering genetic background in PD models and provide valuable insight on how expression of mitochondrial proteins before the onset of neurodegeneration is associated to vulnerability of nigrostriatal dopaminergic neurons. Significance statement Most PD cases are idiopathic and caused by a complex interplay between genetic variants and environmental risk factors. However, the underlying mechanisms remain elusive. Here we show that En1 hemizygosity leads to progressive nigrostriatal degeneration with a loss of dopaminergic neurons in OF1- En1 +/- but that C57- En1 +/- mice only exhibit early signs of nigrostriatal pathology and do not progress to a PD-like phenotype over time. We identified differences in gene expression related to oxidative phosphorylation before the onset of neurodegeneration to be associated to the differential susceptibility to En1 +/- induced PD-like pathology. Our work shows how gene expression changes modulate vulnerability to dopaminergic neurodegeneration in the En1 +/- mouse and reveals putative molecular mechanisms behind the onset and progression of PD. ### Competing Interest Statement The authors have declared no competing interest.