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Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhood

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurodegenerative diseases of childhood. The infantile form, INCL, is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Because thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcysteine, disrupt thioester linkages in a model thioester compound, [14C]palmitoyl∼CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion and raise the possibility that nucleophilic drugs such as phosphocysteamine hold therapeutic potential for INCL.

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Figure 1: Cleavage of thoiester linkages by drugs.
Figure 2: Hydrolysis of [35S]cysteine-labeled lipid-extractable compounds within INCL lymphoblasts by phosphocysteamine.
Figure 3: Electron micrographic evidence for phosphocysteamine-mediated depletion of ceroid deposits in INCL fibroblasts and immortalized lymphoblasts.
Figure 4: Phosphocysteamine-mediated depletion of saposins A and D from immortalized INCL lymphoblasts.
Figure 5: Phosphocysteamine inhibits apoptosis in INCL lymphoblasts.

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Acknowledgements

We thank I. Owens, J.Y. Chou and J.B. Sidbury Jr for critical review of the manuscript; W. Gahl for discussions during this study; M. Hiraiwa for a gift of saposin antibodies; and S. Everett and R. Dreyfuss for technical assistance with photomicrography. This study was supported in part by a `Bench-to-Bedside Award 1999' (to A.B.M) from the Clinical Center of the NIH and by a grant #RO1 NS 389 88-01 (to K.E.W) from the National Institute of Neurological Disorders and Stroke.

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Correspondence to Anil B. Mukherjee.

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Zhang, Z., Butler, J., Levin, S. et al. Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med 7, 478–484 (2001). https://doi.org/10.1038/86554

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