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Gene Review

PPT1  -  palmitoyl-protein thioesterase 1

Homo sapiens

Synonyms: CLN1, INCL, PPT, PPT-1, Palmitoyl-protein hydrolase 1, ...
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Disease relevance of PPT1


Psychiatry related information on PPT1

  • Mutations in palmitoyl protein thioesterase-1 (PPT1) have been found to cause the infantile form of neuronal ceroid lipofuscinosis, which is a lysosomal storage disorder characterized by impaired degradation of fatty acid-modified proteins with accumulation of amorphous granular deposits in cortical neurons, leading to mental retardation and death [6].
  • PREG-S infused at the level of ACh cell bodies (nucleus basalis magnocellularis, NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young animals.Finally, aging related cognitive dysfunctions, particularly those observed in Alzheimer's disease, have also been related to alterations of mechanisms underlying cerebral plasticity [7].
  • The purpose of this study was to determine the relationship between performance on psychometric measures and a modified Physical Performance Test (modified PPT) in older men and women [8].
  • On the PPT, depressives told stories with gloomier emotional tone and psychotics made more perceptual distortions, thematic and interpretive deviations [9].
  • Findings were that (a) PPT encoding and retrieval encoding, separately, assisted later recall: (b) retrieval combined with PPT encoding increased the probability of task performance at final recall; (c) repetition in the absence of retrieval or PPT was less effective; and (d) there was no forgetting between 1 hr and 1 day [10].

High impact information on PPT1

  • 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 [11].
  • Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL [11].
  • 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 [11].
  • 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 [11].
  • The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy [12].

Chemical compound and disease context of PPT1


Biological context of PPT1


Anatomical context of PPT1

  • To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome [23].
  • In leucocytes and fibroblasts from INCL (n = 38) patients we found profound deficiencies of palmitoyl-protein thioesterase I (PPT1), the residual activity was < 5% of mean control activity [22].
  • It is possible that changes in the composition of PL membranes accelerate progression of INCL by altering signalling and membrane trafficking in neurons [24].
  • We also show that TPP-I immunoreactivity is increased in the brain tissue of CLN1 and CLN3 subjects, stronger in glial cells and macrophages than neurons [25].
  • Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the endoplasmic reticulum (ER) in the brain cells of these mice is structurally abnormal [26].

Associations of PPT1 with chemical compounds

  • Characterizing the native substrate(s) for the palmitoyl-protein thioesterase-1 (PPT1) and tripeptidyl peptidase 1 (TPP1), understanding the protein functions encoded by CLN genes, and uncovering the pathological metabolic mechanism for the NCLs are the bases of designing rational treatments for the NCLs [27].
  • We report here that the gene for G14, located in the class III region of the human MHC, encodes a polypeptide with significant sequence similarity to mammalian palmitoyl protein thioesterase (PPT1), an enzyme that removes palmitate from palmitoylated proteins [28].
  • In addition to this function, PPT1 (palmitoyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome [2].
  • In INCL cortex, which had lost 65% of the normal PL content, the proportions of polyunsaturated molecular species, especially the PS and PE that contained docosahexaenoic acid (22:6n-3), were dramatically decreased [24].
  • Compared with the controls, the INCL brains contained proportionally more phosphatidylcholine (PC), and less phosphatidylethanolamine (PE) and phosphatidylserine (PS) [24].

Regulatory relationships of PPT1

  • Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups [29].

Other interactions of PPT1

  • Genomic and proteomic approaches have presently identified eight different forms of NCL (namely, CLN1 through CLN8) based on mutations in specific genes [30].
  • Recently developed Cln1- and Cln3-knockout mouse models share similarities in pathology with the respective human disease [19].
  • Two cases were of the infantile type (CLN1), one case of the juvenile (CLN3) type and one case of the adult (CLN4) type [31].
  • However, we did observe a 40% reduction in peroxisomal particulate (bound) catalase activity in CLN1 and CLN2 fibroblasts, which typically results from organellar lipid accumulation or a membrane abnormality [32].
  • Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00) [33].

Analytical, diagnostic and therapeutic context of PPT1


  1. Molecular diagnosis of and carrier screening for the neuronal ceroid lipofuscinoses. Zhong, N.A., Wisniewski, K.E., Ju, W., Moroziewicz, D.N., Jurkiewicz, A., McLendon, L., Jenkins, E.C., Brown, W.T. Genet. Test. (2000) [Pubmed]
  2. Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Gupta, P., Soyombo, A.A., Atashband, A., Wisniewski, K.E., Shelton, J.M., Richardson, J.A., Hammer, R.E., Hofmann, S.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis. Griffey, M., Bible, E., Vogler, C., Levy, B., Gupta, P., Cooper, J., Sands, M.S. Neurobiol. Dis. (2004) [Pubmed]
  4. Overexpression in colorectal carcinoma of two lysosomal enzymes, CLN2 and CLN1, involved in neuronal ceroid lipofuscinosis. Tsukamoto, T., Iida, J., Dobashi, Y., Furukawa, T., Konishi, F. Cancer (2006) [Pubmed]
  5. Palmitoyl protein thioesterase 1 protects against apoptosis mediated by Ras-Akt-caspase pathway in neuroblastoma cells. Cho, S., Dawson, G. J. Neurochem. (2000) [Pubmed]
  6. The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases, PPT1 and PPT2. Calero, G., Gupta, P., Nonato, M.C., Tandel, S., Biehl, E.R., Hofmann, S.L., Clardy, J. J. Biol. Chem. (2003) [Pubmed]
  7. Individual differences in cognitive aging: implication of pregnenolone sulfate. Mayo, W., George, O., Darbra, S., Bouyer, J.J., Vallée, M., Darnaudéry, M., Pallarès, M., Lemaire-Mayo, V., Le Moal, M., Piazza, P.V., Abrous, N. Prog. Neurobiol. (2003) [Pubmed]
  8. The relation between psychometric test performance and physical performance in older adults. Binder, E.F., Storandt, M., Birge, S.J. J. Gerontol. A Biol. Sci. Med. Sci. (1999) [Pubmed]
  9. Comparing diagnostic validity of the TAT and a new picture projective test. Sharkey, K.J., Ritzler, B.A. Journal of personality assessment. (1985) [Pubmed]
  10. Long-term cued recall of tasks in senile dementia. Bird, M., Kinsella, G. Psychology and aging. (1996) [Pubmed]
  11. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Zhang, Z., Butler, J.D., Levin, S.W., Wisniewski, K.E., Brooks, S.S., Mukherjee, A.B. Nat. Med. (2001) [Pubmed]
  12. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Vesa, J., Hellsten, E., Verkruyse, L.A., Camp, L.A., Rapola, J., Santavuori, P., Hofmann, S.L., Peltonen, L. Nature (1995) [Pubmed]
  13. Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells. Cho, S., Dawson, P.E., Dawson, G. J. Neurosci. Res. (2000) [Pubmed]
  14. Role of palmitoyl-protein thioesterase in cell death: implications for infantile neuronal ceroid lipofuscinosis. Cho, S., Dawson, P.E., Dawson, G. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  15. Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: Implications for treatment of infantile neuronal ceroid lipofuscinosis. Lu, J.Y., Hofmann, S.L. J. Inherit. Metab. Dis. (2006) [Pubmed]
  16. A novel TARP-promoter-based adenovirus against hormone-dependent and hormone-refractory prostate cancer. Cheng, W.S., Kraaij, R., Nilsson, B., van der Weel, L., de Ridder, C.M., Tötterman, T.H., Essand, M. Mol. Ther. (2004) [Pubmed]
  17. Stability of plasma human immunodeficiency virus load in VACUTAINER PPT plasma preparation tubes during overnight shipment. Holodniy, M., Rainen, L., Herman, S., Yen-Lieberman, B. J. Clin. Microbiol. (2000) [Pubmed]
  18. Molecular genetics of the neuronal ceroid lipofuscinoses. Mole, S., Gardiner, M. Epilepsia (1999) [Pubmed]
  19. Early changes in gene expression in two models of Batten disease. Elshatory, Y., Brooks, A.I., Chattopadhyay, S., Curran, T.M., Gupta, P., Ramalingam, V., Hofmann, S.L., Pearce, D.A. FEBS Lett. (2003) [Pubmed]
  20. Structure of the human palmitoyl-protein thioesterase-2 gene (PPT2) in the major histocompatibility complex on chromosome 6p21.3. Soyombo, A.A., Yi, W., Hofmann, S.L. Genomics (1999) [Pubmed]
  21. Genome-wide search for CLN2, the gene causing late-infantile neuronal ceroid-lipofuscinosis (LNCL). Haines, J.L., Boustany, R.M., Worster, T., Ter-Minassian, M., Jondro, P., Lerner, T.J. Am. J. Med. Genet. (1995) [Pubmed]
  22. Pre- and postnatal enzyme analysis for infantile, late infantile and adult neuronal ceroid lipofuscinosis (CLN1 and CLN2). Van Diggelen, O.P., Keulemans, J.L., Kleijer, W.J., Thobois, S., Tilikete, C., Voznyi, Y.V. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  23. The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease. Weimer, J.M., Kriscenski-Perry, E., Elshatory, Y., Pearce, D.A. Neuromolecular Med. (2002) [Pubmed]
  24. Analysis of phospholipid molecular species in brains from patients with infantile and juvenile neuronal-ceroid lipofuscinosis using liquid chromatography-electrospray ionization mass spectrometry. Käkelä, R., Somerharju, P., Tyynelä, J. J. Neurochem. (2003) [Pubmed]
  25. Tripeptidyl-peptidase I in neuronal ceroid lipofuscinoses and other lysosomal storage disorders. Wisniewski, K.E., Kida, E., Walus, M., Wujek, P., Kaczmarski, W., Golabek, A.A. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  26. Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Zhang, Z., Lee, Y.C., Kim, S.J., Choi, M.S., Tsai, P.C., Xu, Y., Xiao, Y.J., Zhang, P., Heffer, A., Mukherjee, A.B. Hum. Mol. Genet. (2006) [Pubmed]
  27. Outlook for future treatment. Zhong, N., Wisniewski, K.E. Adv. Genet. (2001) [Pubmed]
  28. Characterization of a human MHC class III region gene product with S-thioesterase activity. Aguado, B., Campbell, R.D. Biochem. J. (1999) [Pubmed]
  29. High-resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3. Sitter, B., Autti, T., Tyynelä, J., Sonnewald, U., Bathen, T.F., Puranen, J., Santavuori, P., Haltia, M.J., Paetau, A., Polvikoski, T., Gribbestad, I.S., Häkkinen, A.M. J. Neurosci. Res. (2004) [Pubmed]
  30. Biochemistry of neuronal ceroid lipofuscinoses. Junaid, M.A., Pullarkat, R.K. Adv. Genet. (2001) [Pubmed]
  31. Neuronal ceroid lipofuscinosis in the Czech Republic: analysis of 57 cases. Report of the 'Prague NCL group'. Elleder, M., Franc, J., Kraus, J., Nevsímalová, S., Sixtová, K., Zeman, J. Eur. J. Paediatr. Neurol. (1997) [Pubmed]
  32. Mitochondrial abnormalities in CLN2 and CLN3 forms of Batten disease. Dawson, G., Kilkus, J., Siakotos, A.N., Singh, I. Mol. Chem. Neuropathol. (1996) [Pubmed]
  33. Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Mitchison, H.M., Hofmann, S.L., Becerra, C.H., Munroe, P.B., Lake, B.D., Crow, Y.J., Stephenson, J.B., Williams, R.E., Hofman, I.L., Taschner, P.E., Martin, J.J., Philippart, M., Andermann, E., Andermann, F., Mole, S.E., Gardiner, R.M., O'Rawe, A.M. Hum. Mol. Genet. (1998) [Pubmed]
  34. The neuronal ceroid-lipofuscinoses. Goebel, H.H. Seminars in pediatric neurology. (1996) [Pubmed]
  35. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Lönnqvist, T., Vanhanen, S.L., Vettenranta, K., Autti, T., Rapola, J., Santavuori, P., Saarinen-Pihkala, U.M. Neurology (2001) [Pubmed]
  36. Differential regulation of ceramide in lipid-rich microdomains (rafts): antagonistic role of palmitoyl:protein thioesterase and neutral sphingomyelinase 2. Goswami, R., Ahmed, M., Kilkus, J., Han, T., Dawson, S.A., Dawson, G. J. Neurosci. Res. (2005) [Pubmed]
  37. Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). Lehtovirta, M., Kyttälä, A., Eskelinen, E.L., Hess, M., Heinonen, O., Jalanko, A. Hum. Mol. Genet. (2001) [Pubmed]
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