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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE254518 | GEO | 2026/01/26

REPOSITORIES: GEO

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Project description:FOXE3 is a lens specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, we have identified DNAJB1 as a transcriptional target of FOXE3 in a novel pathway that is crucial for development of the anterior segment of the eye. Human Embryonic Kidney (HEK293FT) cells were transfected with the expression vector (pT-RexTM-DEST30) harboring either the wild type or the mutant (C240*) FOXE3 ORF (open reading frame). The experimental design included a total of eight biological replicates of cells expressing the wild type and eight replicates of mutant FOXE3 along with eight non-transfected controls. Cells were harvested 24-hour post-transfection and subjected to total RNA isolation for the preparation of whole transcriptome next-generation sequencing libraries. Initially, we examined the quality of transcriptome libraries on a MiSeq genome analyzer. Subsequent to confirmation of the quality, all libraries were paired-end sequenced (2 x 100 bp) using Illumina TruSeq Cluster V3 flow cell at a concentration of 13.0 pM in two separate lanes (12 bar-coded mRNA pooled libraries in each lane) on a HiSeq 2000 genome analyzer.

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

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