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

Zhongjian Zhang, Jean De B. Butler, Sondra W. Levin, Krystyna E. Wisniewski, Susan S. Brooks, Anil B. Mukherjee

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)478-484
Number of pages7
JournalNature medicine
Volume7
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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