Reduced DNAJB1 expression contributes to aging insubstantia nigra: insights from single-nuclei RNA seq

In this study, we established a comprehensive single-nucleus transcriptomic atlas of human SN across lifespan, from adolescents to centenarians. Notably, we discovered that the protein folding pathway was commonly downregulated among different SN cell types across aging. With orthogonal expression and functional validations, we demonstrated that a decrease in Dnajb1 expression results in reduced potassium ion channels, resulting in elevated neuronal excitability, cellular senescence, reactive astrocytes, ultimately impaired motor balance, and behavioral outputs phenotyping anxiety and depression. Overall design: To investigate the specific molecular changes in the substantia nigra of mice after DNAJB1 knockdown, we used three control groups and a knockdown group for RNA-seq analysis.