PLX139920

GSE141055: Transcriptomic profiling of a CamKII-Dars2 neuronal knockout mouse

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Purpose: Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a rare, slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl-tRNA synthetase (DARS2). While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter, brain stem, and spinal cord, clinical symptoms appear quite variable and a multitude of gene variants have been associated with the disease. Here, Dars2 deletion from CamKII-expressing cortical and hippocampal neurons results in slowly progressive increases in behavioral activity at 5 months, and culminating by 9 months as severe brain atrophy, behavioral dysfunction, reduced corpus callosum thickness, and microglial morphology indicative of neuroinflammation.; Methods: Cortical samples were collected from DARS2-Flox/CamKII-Cre(+) and DARS2-Flox/CamKII-Cre(-) at 14 weeks of age. RNA-seq libraries were prepared using purified RNA isolated from frozen tissue using the RNeasy Mini kit. RNA quality and concentration were assayed using a Fragment Analyzer instrument. RNA-seq libraries were prepared using the TruSeq Stranded mRNA PolyA (Unique Dual Index) kit.. Libraries were sequenced on an Illumina HiSeq 4000 instrument. Samples were taken from N=7 DARS2-Flox/CamKII-Cre(+) and N=6 DARS2-Flox/CamKII-Cre(-) male mice.; Conclusions: RNA-seq based gene expression studies performed prior to the presentation of this severe phenotype reveal the upregulation of several pathways involved in immune activation, cytokine production and signaling, and the defense response regulation. Among these transcripts, Cystatin F (Cst7), a protease inhibitor recognized as a marker of neurodegenerative disease and active demyelination, is upregulated over 200-fold in mutant mice and may serve as a key regulator of disease progression. SOURCE: Ali Fatemi Kennedy Krieger Institute