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  • Title: Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice.
    Author: Wu YP, Proia RL.
    Journal: Proc Natl Acad Sci U S A; 2004 Jun 01; 101(22):8425-30. PubMed ID: 15155903.
    Abstract:
    Sandhoff disease is a prototypical lysosomal storage disorder in which a heritable deficiency of a lysosomal enzyme, beta-hexosaminidase, results in the storage of the enzyme's substrates in lysosomes. As with many of the other lysosomal storage diseases, neurodegeneration is a prominent feature. Although the cellular and molecular pathways that underlie the neurodegenerative process are not yet fully understood, macrophage/microglial-mediated inflammation has been suggested as one possible mechanism. We now show that the expanded macrophage/microglial population in the CNS of Sandhoff disease mice is compounded by the infiltration of cells from the periphery. Coincident with the cellular infiltration was an increased expression of macrophage-inflammatory protein 1alpha (MIP-1alpha), a leukocyte chemokine, in astrocytes. Deletion of MIP-1alpha expression resulted in a substantial decrease in infiltration and macrophage/microglial-associated pathology together with neuronal apoptosis in Sandhoff disease mice. These mice without MIP-1alpha showed improved neurologic status and a longer lifespan. The results indicate that the pathogenesis of Sandhoff disease involves an increase in MIP-1alpha that induces monocytes to infiltrate the CNS, expand the activated macrophage/microglial population, and trigger apoptosis of neurons, resulting in a rapid neurodegenerative course.
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