Infantile neuronal ceroid lipofuscinosis or INCL is a devastating genetically inherited disease caused by a deficiency in palmitoyl-protein thioesterase or PPT1. The hallmarks of the disease are rapid neurologic decline, seizures and blindness due to massive neuronal and retinal cell loss leading to an isoelectric EEG and early death. In this competitive renewal the investigator proposes to do the following. (1) The major metabolic products accumulating in cells from patients with the infantile form of Batten disease will be identified. The investigator states that lipid thioesters derived from acylated proteins accumulate in this disease and that they are neurotoxic. (2) Substrate specificities of PPT1 and PPT2 will be explored based on three-dimensional structure as determined by X-ray crystallography. (3) A circulating inhibitor of PPT1 and PPT2 will be purified from human plasma, then characterized.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-2 (01))
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Spinella, Giovanna M
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Cho, Steve K; Hofmann, Sandra L (2004) pdf1, a palmitoyl protein thioesterase 1 Ortholog in Schizosaccharomyces pombe: a yeast model of infantile Batten disease. Eukaryot Cell 3:302-10
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Lu, Jui-Yun; Verkruyse, Linda A; Hofmann, Sandra L (2002) The effects of lysosomotropic agents on normal and INCL cells provide further evidence for the lysosomal nature of palmitoyl-protein thioesterase function. Biochim Biophys Acta 1583:35-44
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