Deletion of tumor necrosis factor-α ameliorates neurodegeneration in Sandhoff disease mice

Abstract

Sandhoff disease (SD) is a lysosomal storage disorder caused by a lack of a functional β-subunit of the β-hexosaminidase A and B enzymes, leading to the accumulation of gangliosides in the central nervous system (CNS). The Hexb-/- mouse model of SD shows a progressive neurodegenerative phenotype similar to the human equivalent. Previous studies have revealed that Hexb-/- mice suffer from chronic neuroinflammation characterized by microglial activation and expansion. Tumor necrosis factor-α (TNFα), a key modulator of the CNS immune response in models of neurodegeneration, is a hallmark of this activation. In this study, we explore the role of TNFα in the development and progression of SD in mice, by creating a Hexb-/- Tnfα-/- double-knockout mouse. Our results revealed that the double-knockout mice have an ameliorated disease course, with an extended lifespan, enhanced sensorimotor coordination and improved neurological function. TNFα-deficient SD mice also show decreased levels of astrogliosis and reduced neuronal cell death, with no alterations in neuronal storage of gangliosides. Interestingly, temporal microglia activation appears similar between the Hexb-/- Tnfα-/- and SD mice. Evidence is provided for the TNFα activation of the JAK2/STAT3 pathway as a mechanism for astrocyte activation in the disease. Bone marrow transplantation experiments reveal that both CNS-derived and bone marrow-derived TNFα have a pathological effect in SD mouse models, with CNS-derived TNFα playing a larger role. This study reveals TNFα as a neurodegenerative cytokine mediating astrogliosis and neuronal cell death in SD and points to TNFα as a potential therapeutic target to attenuate neuropathogenesis.

Xiaoyaosan exerts anxiolytic-like effects by down-regulating the TNF-α/JAK2-STAT3 pathway in the rat hippocampus

“…Although the role of the activated JAK2-STAT3 pathway in the release of specific cytokines has not yet been fully elucidated, accumulating evidence suggests that TNF-α activates the JAK2-STAT3 signalling pathway 13, 39 . Conversely, JAK2 and STAT3 phosphorylation are limited by the deletion of TNF-α 40 , indicating that TNF-α reliably plays a pivotal role in the activation of JAK/STAT signalling pathway. As shown in the present study, rats exposed to stress that were treated with vehicle (distilled water or dissolvent) showed elevated levels of the p-JAK2 and total JAK2 proteins and the JAK2 mRNA in the hippocampus compared with the control, subsequently increasing the expression of the STAT3 protein and mRNA.…”

Astrocytes and lysosomal storage diseases

“…These changes coincided with significantly increased lifespan, enhanced sensorimotor coordination, and improved neurological function. Interestingly, these improvements in Hexb/Tnf-α double knockout animals were not accompanied by alterations in ganglioside accumulation in neurons (Abo-Ouf et al, 2013). Likewise, increased ERK phosphorylation was shown in a sheep model of infantile NCL, where reactive astrocytes are a prominent feature and associated with aggressive neurodegeneration (Kanninen et al, 2013).…”

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

“…Inflammatory responses are necessary steps for eliminating invading agents, clearing damaged cells and promoting tissue repair (Miwa et al, 1997; Tahara et al, 2006; Ito et al, 2007; Ribes et al, 2009; Szretter et al, 2009); however, uncontrolled neuroinflammation may lead to further tissue injury and neural dysfunction (Lazovic et al, 2005; Choi et al, 2009; Abo-Ouf et al, 2013). Therefore, it has become evident that neuroinflammation represents a significant cause of neurological deficits.…”