Pluto Bioinformatics

GSE150266: Use of mice defective in interferon signaling to distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Bulk RNA sequencing

The type 1 interferon (IFN) response is part of the innate immune response and best known for its role in viral and bacterial infection. However, this pathway is also induced in sterile inflammation such as occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in Gba1. Mice were injected with conduritol B-epoxide, an irreversible inhibitor of acid-beta glucosidase, the enzyme defective in nGD. Quadrat deficient MyTrMaSt mice, where four adaptors of pathogen recognition receptors (PRRs) are deficient, were used to determine the role of the IFN pathway in nGD pathology. Activation of inflammatory and other pathways was analyzed by a variety of methods including RNAseq. Elevation in the expression of PRRs associated with the IFN response was observed in CBE-injected mice. Ablation of upstream pathways leading to IFN production had no therapeutic benefit on the lifespan of nGD mice but attenuated neuroinflammation. Primary and secondary pathological pathways, i.e. those associated or not with mouse lifespan, were distinguished, and a set of ~210 genes including those related to sphingolipid, cholesterol and lipoprotein metabolism, along with a number of inflammatory pathways related to chemokines, TNF, TGF, complement, IL6 and damage associated pathogens were classified as primary pathological pathways, along with some lysosomal and neuronal genes. Although IFN signaling is the top elevated pathway in nGD, we demonstrate that this pathway is not related to mouse viability and is consequently defined as a secondary pathology pathway. By elimination, we defined a number of critical pathways that are directly related to brain pathology in nGD, which in addition to its usefulness in understanding pathophysiological mechanisms may also pave the way for development of novel therapeutic paradigms by targeting such pathways. SOURCE: Ayelet Vardi (ayelet.vardi@weizmann.ac.il) - Weizmann Institute of science