Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035323-06
Application #
6393802
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Spinella, Giovanna M
Project Start
1996-07-01
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
6
Fiscal Year
2001
Total Cost
$234,000
Indirect Cost

  Institution

Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390

  Publications

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
Calero, Guillermo; Gupta, Praveena; Nonato, M Cristina et al. (2003) The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases, PPT1 and PPT2. J Biol Chem 278:37957-64
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
Hofmann, Sandra L; Atashband, Armita; Cho, Steve K et al. (2002) Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2). Curr Mol Med 2:423-37
Rush, Jeffrey S; Cho, Steve K; Jiang, Songmin et al. (2002) Identification and characterization of a cDNA encoding a dolichyl pyrophosphate phosphatase located in the endoplasmic reticulum of mammalian cells. J Biol Chem 277:45226-34
Gupta, P; Hofmann, S L (2002) Neuronal ceroid lipofuscinosis/Batten disease: the lysosomal proteinoses. Mol Psychiatry 7:434-6
Hofmann, S L; Das, A K; Lu, J Y et al. (2001) Positional candidate gene cloning of CLN1. Adv Genet 45:69-92
Das, A K; Bellizzi 3rd, J J; Tandel, S et al. (2000) Structural basis for the insensitivity of a serine enzyme (palmitoyl-protein thioesterase) to phenylmethylsulfonyl fluoride. J Biol Chem 275:23847-51
Bellizzi 3rd, J J; Widom, J; Kemp, C et al. (2000) The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A 97:4573-8
Bennett, M J; Hofmann, S L (1999) The neuronal ceroid-lipofuscinoses (Batten disease): a new class of lysosomal storage diseases. J Inherit Metab Dis 22:535-44

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