Infantile neuronal ceroid lipofuscinosis (INCL; infantile Batten disease) is an inherited paediatric neurodegenerative disease. INCL is caused by a deficiency in the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) and is thus classified as a lysosomal storage disease. Pathological examination of both human and murine INCL brains reveals progressive, widespread neuroinflammation. In fact, astrocyte activation appears to be the first histological sign of disease. However, the role of astrocytosis in INCL was poorly understood. The hallmark of astrocyte activation is the up-regulation of intermediate filaments, such as glial fibrillary acidic protein (GFAP) and vimentin. The role of astrocytosis in INCL was studied in a murine model lacking PPT1 and the intermediate filaments GFAP and vimentin (triple-knockout). This murine model of INCL with attenuated astrocytosis had an exacerbated pathological and clinical phenotype. The triple-knockout mouse had a significantly shortened lifespan, and accelerated cellular and humoural neuroinflammatory response compared with the parental PPT1−/− mouse. The data obtained from the triple-knockout mouse strongly suggest that astrocyte activation plays a beneficial role in early INCL disease progression. A more thorough understanding of the glial responses to lysosomal enzyme deficiencies and the accumulation of undergraded substrates will be crucial to developing effective therapeutics.
Conference Article| September 18 2014
Astrocytosis in infantile neuronal ceroid lipofuscinosis: friend or foe?
Mark S. Sands
Mark S. Sands 1
*Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, U.S.A.
†Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, U.S.A.
1To whom correspondence should be addressed (firstname.lastname@example.org).
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Charles Shyng, Mark S. Sands; Astrocytosis in infantile neuronal ceroid lipofuscinosis: friend or foe?. Biochem Soc Trans 1 October 2014; 42 (5): 1282–1285. doi: https://doi.org/10.1042/BST20140188
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