title: Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice.
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.
authors.affiliation: Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D001835:Body Weight; D002490:Central Nervous System / Q000166:cytology* / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008017:Life Expectancy; D019402:Macrophage Inflammatory Proteins / Q000235:genetics* / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D012497:Sandhoff Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D016177:Macrophage-1 Antigen; D001619:beta-N-Acetylhexosaminidases