{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:49:53Z","timestamp":1792601393549,"version":"4.5.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,6]]},"abstract":"<jats:p>Sandhoff disease is a prototypical lysosomal storage disorder in which a heritable deficiency of a lysosomal enzyme, \u03b2-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 1\u03b1 (MIP-1\u03b1), a leukocyte chemokine, in astrocytes. Deletion of MIP-1\u03b1 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-1\u03b1 showed improved neurologic status and a longer lifespan. The results indicate that the pathogenesis of Sandhoff disease involves an increase in MIP-1\u03b1 that induces monocytes to infiltrate the CNS, expand the activated macrophage\/microglial population, and trigger apoptosis of neurons, resulting in a rapid neurodegenerative course.<\/jats:p>","DOI":"10.1073\/pnas.0400625101","type":"journal-article","created":{"date-parts":[[2004,5,20]],"date-time":"2004-05-20T21:47:55Z","timestamp":1085089675000},"page":"8425-8430","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":157,"title":["Deletion of macrophage-inflammatory protein 1\u03b1 retards neurodegeneration in Sandhoff disease mice"],"prefix":"10.1073","volume":"101","author":[{"given":"Yun-Ping","family":"Wu","sequence":"first","affiliation":[{"name":"Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Proia","sequence":"additional","affiliation":[{"name":"Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,5,20]]},"reference":[{"key":"e_1_3_2_1_2","first-page":"3827","volume":"3","year":"2001","unstructured":"Gravel, R. 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