Induction of the type I interferon response in neurological forms of Gaucher disease

Abstract

BackgroundNeuroinflammation is a key phenomenon in the pathogenesis of many neurodegenerative diseases. Understanding the mechanisms by which brain inflammation is engaged and delineating the key players in the immune response and their contribution to brain pathology is of great importance for the identification of novel therapeutic targets for these devastating diseases. Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the GBA1 gene and is a significant risk factor for Parkinson’s disease; in some forms of Gaucher disease, neuroinflammation is observed.MethodsAn unbiased gene profile analysis was performed on a severely affected brain area of a neurological form of a Gaucher disease mouse at a pre-symptomatic stage; the mouse used for this study, the Gbaflox/flox; nestin-Cre mouse, was engineered such that GBA1 deficiency is restricted to cells of neuronal lineage, i.e., neurons and macroglia.ResultsThe 10 most up-regulated genes in the ventral posteromedial/posterolateral region of the thalamus were inflammatory genes, with the gene expression signature significantly enriched in interferon signaling genes. Interferon β levels were elevated in neurons, and interferon-stimulated genes were elevated mainly in microglia. Interferon signaling pathways were elevated to a small extent in the brain of another lysosomal storage disease mouse model, Krabbe disease, but not in Niemann-Pick C or Sandhoff mouse brain. Ablation of the type I interferon receptor attenuated neuroinflammation but had no effect on GD mouse viability.ConclusionsOur results imply that the type I interferon response is involved in the development of nGD pathology, and possibly in other lysosomal storage diseases in which simple glycosphingolipids accumulate, and support the notion that interferon signaling pathways play a vital role in the sterile inflammation that often occurs during chronic neurodegenerative diseases in which neuroinflammation is present.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0570-2) contains supplementary material, which is available to authorized users.

Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease

“…Gene expression profiling microarray analysis was performed as described [9], but using RNA from the VPM/ VPL region of Gba flox/WT ;nestin-Cre mice and Gba flox/flox ; nestin-Cre mice at 10 days of age.…”

“…The most consistent neuropathological finding reported in human nGD patients is accumulation of lipid-laden macrophages as well as neuronal loss and neuroinflammation [3]. The use of mouse models of nGD [4][5][6] has resulted in the discovery of additional pathways involved in neuropathology, such as neuronal loss [7], neuroinflammation [8] and activation of specific signaling pathways [9,10]. The Gba flox/flox ; nestin-Cre mice [4], a commonly used nGD mouse model, exhibits rapid motor dysfunction associated with severe neuroinflammation and neuronal loss starting at 14 days of age, and develops paralysis by 21 days.…”

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

“…Nevertheless, the precise contribution of neuroinflammation to disease progression is currently unclear (Vitner et al, 2014(Vitner et al, , 2016. proposed to impact pathogenesis (Archer et al, 2014;Arfi et al, 2011;Wilkinson et al, 2012).…”

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

“…A recent study by Taylor and colleagues has shown increased expression of IFN-I in the brains of patients with Alzheimer's disease (AD; Taylor et al, 2014). Moreover, findings in mouse models for Gaucher disease and Krabbe disease suggest that IFN-I contribute to the neuroinflammation present in some neurodegenerative lysosomal storage diseases (Vitner et al, 2016). This is contrasted by other studies that have yielded conflicting results, indicating a neuroprotective role for IFN-I in the murine and human CNS with AD-like neurodegeneration (Ejlerskov et al, 2015;Grimaldi et al, 2014).…”