Transcriptome and microRNA profiling reveals deregulated microRNAs and mRNAs in the brain of neuronopathic Gaucher disease mice. Y. Sun1,2, N. Dasgupta1, Y. Xu1,2, B. Liou1, R. Li1,2, Y. Peng1, M. Pandey1,2, S. Tinch1, V. Inskeep1, G. A. Grabowski3 1) Divison of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH; 2) Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH 45229; 3) Synageva BioPharma Corp, Lexington, MA 02421.

   Gaucher disease is caused by deficiency of lysosomal acid -glucosidase (GCase) leading to accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the viscera and CNS. CNS pathogenesis results from neuronal degeneration propagated by the toxic effects of GS and GC. To understand the pathogenic mechanisms in neuronopathic Gaucher disease (nGD), global profiles of differentially expressed mRNAs (DEGs) and microRNA (DEmiRs) were analysed using a viable nGD mice (4L;C*). This model develops neurological deficits analogous to sub-acute human nGD. The brain of 4L;C* mice accumulates GC and GS with resultant inflammation and decreased mitochondrial function. DEGs and DEmiRs were analyzed using isolated RNA from cerebral cortex (CO), brain stem (BS), midbrain (MID) and cerebellum (CB) of age and strain matched 4L;C* and WT mice using RNASeq. These brain regions were also analyzed in 4L;C* mice treated with isofagomine, a pharmacologic chaperone for GCase. Analyses showed region specific and common DEGs and DEmiRs in CO, BS, MID or CB. The predicted DEmiR-target DEGs with inverse correlations of microRNA represented about 46%, 47%, 58% and 51% of total DEGs in CO, BS, MID and CB, respectively. The DEGs regional specific deregulation in 4L;C* brains was significantly altered after isofagomine treatment. Isofagomine treatment also normalized part of the abnormalities of DEmiRs and their target DEGs, but also induced additional changes in DEmiRs expression. Total altered DEGs from 4L;C* brain regions were classified to two major groups: inflammatory and non-inflammatory. The inflammatory DEGs were about 25% of total DEGs in each brain regions. IPA analyses of all brain regions showed that top functional pathways of inflammatory DEGs include the roles of macrophages, dendritic cell maturation, acute phase responses, and NK-kB signaling. The top functional groups of non-inflammatory DEGs were eIF2 signaling, axonal guidance signaling, mTOR signaling, neurological disease and mitochondrial system. These analyses demonstrate that the neurodegenerative phenotypes in 4L;C* mice were associated with regional brain transcriptional changes in mRNAs and microRNAs. These abnormalities were broadly related to neuronal functions, such as neuronal differentiation, synaptic plasticity, mitochondria function and inflammation. This study provides new insights into the pathological mechanisms of nGD and the molecular basis for development of novel therapeutic targets.