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. 1998 Sep 15;334(Pt 3):547–551. doi: 10.1042/bj3340547

Specific alterations in levels of mannose 6-phosphorylated glycoproteins in different neuronal ceroid lipofuscinoses.

D E Sleat 1, I Sohar 1, P S Pullarkat 1, P Lobel 1, R K Pullarkat 1
PMCID: PMC1219721  PMID: 9729460

Abstract

Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is generated on newly synthesized lysosomal proteins. This modification is specifically recognized by two Man-6-P receptors that direct the vesicular transport of the lysosomal enzymes from the Golgi to a prelysosomal compartment. The Man-6-P is rapidly removed in the lysosome of most cell types; however, in neurons the Man-6-P modification persists. In this study we have examined the spectrum of Man-6-P-containing glycoproteins in brain specimens from patients with different neuronal ceroid lipofuscinoses (NCLs), which are progressive neurodegenerative disorders with established links to defects in lysosomal catabolism. We find characteristic alterations in the Man-6-P glycoproteins in specimens from late-infantile (LINCL), juvenile (JNCL) and adult (ANCL) patients. Man-6-P glycoproteins in LINCL patients were similar to controls, with the exception that the band corresponding to CLN2, a recently identified lysosomal enzyme whose deficiency results in this disease, was absent. In an ANCL patient, two Man-6-P glycoproteins were elevated in comparison with normal controls, suggesting that this disease also results from a perturbation in lysosomal hydrolysis. In JNCL, total levels of Man-6-P glycoproteins were 7-fold those of controls. In general this was reflected by increased lysosomal enzyme activities in JNCL but three Man-6-P glycoproteins were elevated to an even greater degree. These are CLN2 and the unidentified proteins that are also highly elevated in the ANCL.

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Selected References

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  1. Camp L. A., Hofmann S. L. Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras. J Biol Chem. 1993 Oct 25;268(30):22566–22574. [PubMed] [Google Scholar]
  2. Hellsten E., Vesa J., Olkkonen V. M., Jalanko A., Peltonen L. Human palmitoyl protein thioesterase: evidence for lysosomal targeting of the enzyme and disturbed cellular routing in infantile neuronal ceroid lipofuscinosis. EMBO J. 1996 Oct 1;15(19):5240–5245. [PMC free article] [PubMed] [Google Scholar]
  3. Janes R. W., Munroe P. B., Mitchison H. M., Gardiner R. M., Mole S. E., Wallace B. A. A model for Batten disease protein CLN3: functional implications from homology and mutations. FEBS Lett. 1996 Dec 9;399(1-2):75–77. doi: 10.1016/s0014-5793(96)01290-2. [DOI] [PubMed] [Google Scholar]
  4. Järvelä I., Sainio M., Rantamäki T., Olkkonen V. M., Carpén O., Peltonen L., Jalanko A. Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum Mol Genet. 1998 Jan;7(1):85–90. doi: 10.1093/hmg/7.1.85. [DOI] [PubMed] [Google Scholar]
  5. Khan K. M., Brooks S. S., Pullarkat R. K. Abnormal acid phosphatases in neuronal ceroid-lipofuscinoses. Am J Med Genet. 1995 Jun 5;57(2):285–289. doi: 10.1002/ajmg.1320570234. [DOI] [PubMed] [Google Scholar]
  6. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  7. Meunier B., Rodriguez-Lopez J. N., Smith A. T., Thorneley R. N., Rich P. R. Redox- and anion-linked protonation sites in horseradish peroxidase: analysis of distal haem pocket mutants. Biochem J. 1998 Feb 15;330(Pt 1):303–309. doi: 10.1042/bj3300303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Prasad V. V., Pullarkat R. K. Brain lysosomal hydrolases in neuronal ceroid-lipofuscinoses. Mol Chem Neuropathol. 1996 Oct-Dec;29(2-3):169–179. doi: 10.1007/BF02815000. [DOI] [PubMed] [Google Scholar]
  9. Pullarkat R. K., Zawitosky S. E. Glycoconjugate abnormalities in the ceroid-lipofuscinoses. J Inherit Metab Dis. 1993;16(2):317–322. doi: 10.1007/BF00710274. [DOI] [PubMed] [Google Scholar]
  10. Sleat D. E., Donnelly R. J., Lackland H., Liu C. G., Sohar I., Pullarkat R. K., Lobel P. Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis. Science. 1997 Sep 19;277(5333):1802–1805. doi: 10.1126/science.277.5333.1802. [DOI] [PubMed] [Google Scholar]
  11. Sleat D. E., Sohar I., Lackland H., Majercak J., Lobel P. Rat brain contains high levels of mannose-6-phosphorylated glycoproteins including lysosomal enzymes and palmitoyl-protein thioesterase, an enzyme implicated in infantile neuronal lipofuscinosis. J Biol Chem. 1996 Aug 9;271(32):19191–19198. doi: 10.1074/jbc.271.32.19191. [DOI] [PubMed] [Google Scholar]
  12. Valenzano K. J., Kallay L. M., Lobel P. An assay to detect glycoproteins that contain mannose 6-phosphate. Anal Biochem. 1993 Feb 15;209(1):156–162. doi: 10.1006/abio.1993.1096. [DOI] [PubMed] [Google Scholar]
  13. Verkruyse L. A., Hofmann S. L. Lysosomal targeting of palmitoyl-protein thioesterase. J Biol Chem. 1996 Jun 28;271(26):15831–15836. doi: 10.1074/jbc.271.26.15831. [DOI] [PubMed] [Google Scholar]
  14. Vesa J., Hellsten E., Verkruyse L. A., Camp L. A., Rapola J., Santavuori P., Hofmann S. L., Peltonen L. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature. 1995 Aug 17;376(6541):584–587. doi: 10.1038/376584a0. [DOI] [PubMed] [Google Scholar]

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