Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease

Abstract

Gaucher's disease, the most common lysosomal storage disorder, is caused by the defective activity of glucocerebrosidase, the lysosomal hydrolase that degrades glucosylceramide. The neuronopathic forms of Gaucher's disease are characterized by severe neuronal loss, astrocytosis and microglial proliferation, but the cellular and molecular pathways causing these changes are not known. In the current study, we delineate the role of neuroinflammation in the pathogenesis of neuronopathic Gaucher's disease and show significant changes in levels of inflammatory mediators in the brain of a neuronopathic Gaucher's disease mouse model. Levels of messenger RNA expression of interleukin -1β, tumour necrosis factor-α, tumour necrosis factor-α receptor, macrophage colony-stimulating factor and transforming growth factor-β were elevated by up to ∼30-fold, with the time-course of the increase correlating with the progression of disease severity. The most significant elevation was detected for the chemokines CCL2, CCL3 and CCL5. Blood-brain barrier disruption was also evident in mice with neuronopathic Gaucher's disease. Finally, extensive elevation of nitrotyrosine, a hallmark of peroxynitrite (ONOO(-)) formation, was observed, consistent with oxidative damage caused by macrophage/microglia activation. Together, our results suggest a cytotoxic role for activated microglia in neuronopathic Gaucher's disease. We suggest that once a critical threshold of glucosylceramide storage is reached in neurons, a signalling cascade is triggered that activates microglia, which in turn releases inflammatory cytokines that amplify the inflammatory response, contributing to neuronal death.

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…Gaucher disease patients showed elevated serum TNF-α levels, and in the fetal brains of a Gaucher disease mouse model, TNF-α levels (as well as the levels of different other pro-inflammatory cytokines) were increased [181,182]. Also, after birth, TNF-α and TNFR1 were found to be upregulated in the brains of Gaucher disease mice with increasing age and disease severity [183]. All in all, there are many conditions with neurodegenerative components in which TNF-α signaling may significantly contribute to neuropathological processes, and more research focusing on TNF-α signaling via either TNFR1 and TNFR2 is warranted.…”

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

“…Importantly, iron chelation has been shown to desensitize cells to oxidative stress and increase lysosomal stability ( 74 ). Interestingly, one of the often observed characteristics of cellular pathology in LSDs is the marked elevation of oxidative stress, and ROS have been found elevated in several LSDs, including Fabry disease, microglia of Gaucher disease, GM1 and GM2 gangliosidoses, and Niemann-Pick disease type C, providing another mechanistic clue to the loss of lysosomal integrity and cell death processes occurring in LSDs (75)(76)(77)(78).…”

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

“…In fact, a homozygous mutation in human β-glucocerebrosidase (GBA1), a crucial enzyme degrading β-GlcCer, leads to Gaucher disease because of a reduction in enzyme activity that causes accumulation of β-GlcCer (19). Gaucher disease is characterized by systemic inflammation, which presents hepatosplenomegaly or neurodegeneration (20)(21)(22)(23)(24). However, the molecular mechanisms that link excessive β-GlcCer to inflammatory responses are not yet understood.…”