| First Author | Abo-Ouf H | Year | 2013 |
| Journal | Hum Mol Genet | Volume | 22 |
| Issue | 19 | Pages | 3960-75 |
| PubMed ID | 23727835 | Mgi Jnum | J:201101 |
| Mgi Id | MGI:5510931 | Doi | 10.1093/hmg/ddt250 |
| Citation | Abo-Ouf H, et al. (2013) Deletion of tumor necrosis factor-alpha ameliorates neurodegeneration in Sandhoff disease mice. Hum Mol Genet 22(19):3960-75 |
| abstractText | Sandhoff disease (SD) is a lysosomal storage disorder caused by a lack of a functional beta-subunit of the beta-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-alpha (TNFalpha), 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 TNFalpha in the development and progression of SD in mice, by creating a Hexb(-/-)Tnfalpha(-/-) 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. TNFalpha-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(-/-)Tnfalpha(-/-)and SD mice. Evidence is provided for the TNFalpha 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 TNFalpha have a pathological effect in SD mouse models, with CNS-derived TNFalpha playing a larger role. This study reveals TNFalpha as a neurodegenerative cytokine mediating astrogliosis and neuronal cell death in SD and points to TNFalpha as a potential therapeutic target to attenuate neuropathogenesis. |
