Deletion of macrophage-inflammatory protein 1α retards neurodegeneration in Sandhoff disease mice
Abstract
Sandhoff disease is a prototypical lysosomal storage disorder in which a heritable deficiency of a lysosomal enzyme, β-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 1α (MIP-1α), a leukocyte chemokine, in astrocytes. Deletion of MIP-1α 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-1α showed improved neurologic status and a longer lifespan. The results indicate that the pathogenesis of Sandhoff disease involves an increase in MIP-1α that induces monocytes to infiltrate the CNS, expand the activated macrophage/microglial population, and trigger apoptosis of neurons, resulting in a rapid neurodegenerative course.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- June 2004
- DOI:
- 10.1073/pnas.0400625101
- Bibcode:
- 2004PNAS..101.8425W
- Keywords:
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- Medical Sciences