Sex differences in gene expression with galactosylceramide treatment in Cln3Δex7/8 mice

Abstract

Background CLN3 disease is caused by mutations in the CLN3 gene. The purpose of this study is to discern global expression patterns reflecting therapeutic targets in CLN3 disease. Methods Differential gene expression in vehicle-exposed mouse brain was determined after intraperitoneal vehicle/Galactosylceramide (GalCer) injections for 40 weeks with GeneChip Mouse Genome 430 2.0 arrays. Results Analysis identified 66 genes in male and 30 in female brains differentially expressed in Gal-Cer-treated versus vehicle-exposed Cln3 Δex7/8 mice. Gene ontology revealed aberrations of biological function including developmental, cellular, and behavioral processes. GalCer treatment altered pathways of long-term potentiation/depression, estrogen signaling, synaptic vesicle cycle, ErbB signaling, and prion diseases in males, but prolactin signaling, selenium compound metabolism and steroid biosynthesis in females. Gene-gene network analysis highlighted networks functionally pertinent to GalCer treatment encompassing motor dysfunction, neurodegeneration, memory disorder, inflammation and astrogliosis in males, and, cataracts, inflammation, astrogliosis, and anxiety in females. Conclusions This study sheds light on global expression patterns following GalCer treatment of Cln3 Δex7/8 mice. Understanding molecular effects of GalCer on mouse brain gene expression, paves the way for personalized strategies for treating this debilitating disease in humans.

Sex-split analysis of pathology and motor-behavioral outcomes in a mouse model of CLN8-Batten disease reveals an increased disease burden and trajectory in female Cln8mnd mice

“…The utilization of murine models in Batten disease research has greatly expanded the ability to investigate sex differences in this family of diseases, in addition to highlighting the importance of sex as a factor to be considered when designing and analyzing therapeutic trials [ 29 ]. For instance, sex-dependent differences in gene expression response to galactosylceramide were found in the Cln3 Δex7/8 murine model [ 30 ]. Further, Poppens et al described female Cln6 nclf mice to experience accelerated disease progression, more severe behavioral issues and motor decline, and differences in histopathological effects [ 31 ].…”