Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Abstract

Background: 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 that which occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in GBA. Methods: Mice were injected with conduritol B-epoxide, an irreversible inhibitor of acid beta-glucosidase, the enzyme defective in nGD. MyTrMaSt null 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. Results: 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 survival) 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 microglia were classified as primary pathological pathways, along with some lysosomal and neuronal genes. Conclusions: 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 the development of novel therapeutic paradigms by targeting such pathways.

Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways

“…Neuroinflammation, activation of the complement system, and defective myelination were also observed in the MLIV brain. For the former, noticeable pathways of neuroinflammation include activation of the interferon pathway, as previously demonstrated in Mcoln1 −/− microglia [53] and astrocytes [38], and similar to that previously observed in another LSD, Gaucher disease [63,71]. However, in Gaucher Fig.…”

“…APOD and APOE, are involved in the removal of lipids during nerve cell degeneration [62], which may be of importance in demyelination. Moreover, levels of two PLIN proteins (PLIN 3 and 4) were elevated in the MLIV brain and in neuronal forms of Gaucher disease [63,64]. Lipid droplets have been implicated in neurodegeneration [65,66] including in Parkinson's disease, which suggest that they play a broad role in neurodegenerative diseases.…”

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

“…Incubation of the GD macrophages with recombinant GCase (rGCase) also prevented the rC5a-induced increase in TNF-α production, demonstrating that the rC5a effects observed were not an artifact of the iPSC system, but were indeed due to the loss of GCase in the mutant cells (Figure 2), which leads to substrate accumulation. Our results suggest that in the absence of functional GCase, rC5a stimulation triggers an abnormal increase in cytokine production, in agreement with the idea that GCase enzyme activity is required for a balanced inflammatory response of macrophages [18,[40][41][42][43].…”

“…Our analysis showed that several genes involved in cholesterol biosynthesis, fatty acid degradation, and lipoprotein metabolism were downregulated in GD macrophages (e.g., DHCR7 , MSMO1 , SLC27A2 , CYP51A1 , FASN, APOC1 , and APOE ) ( Figure 4 ) [ 43 ]. Genetic defects in cholesterol metabolism are primarily associated with neuropathology.…”

“…Genetic defects in cholesterol metabolism are primarily associated with neuropathology. In particular, DHCR7 and MSMO1 were previously found to be down-regulated upon injection of mice with conduritol B-epoxide (CBE), an irreversible inhibitor of GCase that recapitulates a number of alterations found in GD [ 43 ]. Thus, the defective lipid biosynthesis and lipoprotein metabolism of human iPSC-macrophages also reflects known GD pathology.…”