Deletion of macrophage-inflammatory protein 1α retards neurodegeneration in Sandhoff disease mice
- Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
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Edited by Elizabeth F. Neufeld, University of California School of Medicine, Los Angeles, CA (received for review January 28, 2004)
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.
Footnotes
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↵ * To whom correspondence should be addressed at: National Institutes of Health, Building 10, Room 9N-314, 10 Center Drive, MSC 1821, Bethesda, MD 20892-1821. E-mail: proia{at}nih.gov.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: MIP, macrophage-inflammatory protein; TNF-α, tumor necrosis factor α; HRP, horseradish peroxidase; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; GFAP, glial fibrillary acidic protein.
