Dysregulated angiogenin and related pathways in the ventral midbrain of “redhead” mice with MC1R disruption

A relationship between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and Parkinson's disease (PD) has been previously suggested. The present study aims to investigate the gene expression pattern in the ventral midbrain (VMB) of MC1R extension (<i>MC1R</i>^e/e) mice to provide insights into the underlying mechanism of dopaminergic neuron loss in these mice. RNA sequencing (RNA-seq) was conducted on VMB tissues from <i>MC1R</i>^e/e mice and their wild-type (WT) C57BL/6J littermates. Gene expression levels and pathway activity were assessed using differential gene expression analysis, Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). To validate the RNA-seq results, real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and ELISA were performed. Our analyses found significant transcriptomic differences in the VMB between <i>MC1R</i>^e/e mice and WT controls. Several immune response-related pathways were identified to be downregulated in the <i>MC1R</i>^e/e group. Angiogenin (ANG) was implicated in several of the enriched pathways in <i>MC1R</i>^e/e mice. Furthermore, <i>Ang</i> was found to be significantly downregulated in the VMB of <i>MC1R</i>^e/e mice, which was confirmed at both mRNA and protein levels. There was no significant difference in Ang protein levels in the serum of <i>MC1R</i>^e/e and WT mice. Our results suggest a differential gene expression pattern in the VMB as a result of MC1R mutation. Notably, lower Ang expression may be involved in the neuronal loss observed in the VMB of the <i>MC1R</i>^e/e mice.<b>NEW & NOTEWORTHY</b> Our study identifies reduced angiogenin (<i>Ang</i>) expression in the ventral midbrain (VMB) of <i>MC1R</i>^e/e mice, validated through RNA-seq, RT-qPCR, and Western blot. This CNS-specific downregulation suggests localized regulatory mechanisms linked to neuroprotection and Parkinson's disease (PD) pathogenesis. <i>Ang</i>'s role in neurodegeneration, angiogenesis, and oxidative stress responses highlights its therapeutic potential in PD. These findings provide critical insights into <i>Ang</i>'s CNS-specific function and underscore the importance of further research into its mechanistic role in PD.