Abstract
This study evaluated whether GM2 ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB−/− mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB−/− mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB−/− mice from GM2 neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM2 presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored.
Highlights
The pathognomonic feature of Sandhoff disease is GM2 ganglioside storage primarily in neurons
Conditional restoration of β-hexosaminidase in neurons rescued HexB−/− mice from GM2 ganglioside storage Conditional restitution of β-hexosaminidase in the neurons of HexB−/− mice was accomplished by driving the expression of the human HEXB cDNA by the neuron specific Thy1 promoter in transgenic mice (Figure 1A)
In order to elucidate the role of GM2 ganglioside storage in neurodegeneration and neuroinflammation, we restored β-hexosaminidase selectively in the neurons HexB−/− mice targeting the expression of the human
Summary
The pathognomonic feature of Sandhoff disease is GM2 ganglioside storage primarily in neurons. Catabolism of GM2 ganglioside in mammalian cells is undertaken by β-hexosaminidase, a lysosomal acidic hydrolase. HEXA (α/β) catabolizes GM2 presented by a third protein named GM2 activator. Human patients with HEXA (Tay-Sachs) or HEXB (Sandhoff) mutations develop storage of GM2 ganglioside in the lysosomes due to the lack of HEXA (α/β) enzyme activity [1]. HEXA enzyme is present in all cell types and tissues, neurons are characterized the human either HEXA or HEXB mutations can cause GM2 storage. For these reasons, the HexB−/− knockout mouse is widely accepted as the appropriate animal model in the study of GM2 gangliosidosis [1,2]
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