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Lysosomal ceroid depletion by a small molecule: therapeutic implications for an inherited childhood neurodegenerative storage disease

Wednesday, October 26, 2011 — Poster Session IV

2:00 p.m. – 4:00 p.m.

Natcher Conference Center



* FARE Award Winner


  • C Sarkar
  • G Chandra
  • Z Zhang
  • S Peng
  • AB Mukherjee


Infantile neuronal ceroid lipofuscinosis (INCL) is one of the most lethal childhood neurodegenerative storage disorders. Children afflicted with the disease are normal at birth but around age two, they develop psychomotor retardation and retinal blindness. By age four, these children loose brain activity and remain vegetative for another 8-10 years before death. The disease is caused by mutations in the gene encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1 cleaves thioester linkages in palmitoylated proteins facilitating their degradation. Lack of PPT1 in INCL causes accumulation of palmitoylated proteins (constituent of ceroid). Currently there is no effective treatment for INCL. Hydroxylamine (HA), a small molecule, can cleave thioester linkages in s-acylated proteins with high specificity. However, toxicity precludes its clinical application. Here we identify a non-toxic HA-derivative, N-t-Butylhydroxylamine (NtBuHA) which cleaves thioester linkages in s-acylated proteins and mediates ceroid depletion in cultured INCL cells. Further, NtBuHA treatment depleted ceroid, alleviated oxidative stress and inhibited apoptosis in the brain of Ppt1-KO mice an animal model of INCL. Importantly, NtBuHA-treatment prevented deterioration of motor function in these mice. Our results define a novel pharmacological approach to lysosomal ceroid depletion and provide the proof of principle that small molecules like NtBuHA may have therapeutic potential for INCL.

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