Abstract

Neuronal ceroid lipofuscinosis (NCL) is a group of hereditary, autosomal recessive, degenerative brain diseases that are characterized by the accumulation of lipid storage bodies resembling pigments that form with advanced age in normal tissues. The most severe form, infantile NCL (INCL) is caused by defects in a lysosomal enzyme, palmitoyl-protein thioesterase (PPT). This enzyme removes covalently-attached fatty acids from cystein residues in proteins. The defective lysosomal thioesterase activity leads to the accumulation of small, protein-derived, cystein lipid thioesters in infantile NCL cells. The final result is neuronal degeneration and clinical """"""""brain death"""""""" by the age of 3 years in most patients. INCL is most prevalent in the Finnish population where a single point mutation in PPT accounts for 40/42 cases. The incidence of PPT deficiency among NCL patients outside of Finland is unknown. A major goal of this proposal is to determine the frequency of PPT deficiency in the US. NCL population and to define the unique characteristics of these patients. Furthermore, mutations in the PPT gene will be characterized in PPT-deficient subjects and correlated the clinical phenotype. The information gained from the study of naturally-occurring mutations will be used to explore structure-function relationships in the PPT enzyme. Finally, the role of a PPT homolog (PPT-2) will be investigated in NCL and other neurodegenerative diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036867-02
Application #
2714656
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Small, Judy A
Project Start
1997-07-28
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
2
Fiscal Year
1998
Total Cost
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

Dearborn, Joshua T; Ramachandran, Subramania; Shyng, Charles et al. (2016) Histochemical localization of palmitoyl protein thioesterase-1 activity. Mol Genet Metab 117:210-6
Hu, Jie; Lu, Jui-Yun; Wong, Andrew M S et al. (2012) Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol Genet Metab 107:213-21
Li, Yi; Hu, Jie; Höfer, Klemens et al. (2010) DHHC5 interacts with PDZ domain 3 of post-synaptic density-95 (PSD-95) protein and plays a role in learning and memory. J Biol Chem 285:13022-31
Lu, Jui-Yun; Hu, Jie; Hofmann, Sandra L (2010) Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis. Mol Genet Metab 99:374-8
Qiao, Xingwen; Lu, Jui-Yun; Hofmann, Sandra L (2007) Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response. BMC Neurosci 8:95
Lu, J-Y; Hofmann, S L (2006) Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: implications for treatment of infantile neuronal ceroid lipofuscinosis. J Inherit Metab Dis 29:119-26
Lu, Jui-Yun; Hofmann, Sandra L (2006) Thematic review series: lipid posttranslational modifications. Lysosomal metabolism of lipid-modified proteins. J Lipid Res 47:1352-7
Virmani, Tuhin; Gupta, Praveena; Liu, Xinran et al. (2005) Progressively reduced synaptic vesicle pool size in cultured neurons derived from neuronal ceroid lipofuscinosis-1 knockout mice. Neurobiol Dis 20:314-23
Cho, Steve K; Gao, Ningguo; Pearce, David A et al. (2005) Characterization of lipid-linked oligosaccharide accumulation in mouse models of Batten disease. Glycobiology 15:637-48
Bible, Ellen; Gupta, Praveena; Hofmann, Sandra L et al. (2004) Regional and cellular neuropathology in the palmitoyl protein thioesterase-1 null mutant mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 16:346-59

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