Choi YG, Kim JI, Jeon YC, Park SJ, Choi EK, Rubenstein R, Kascsak RJ, Carp RI, Kim YS.
Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies.
J Biol Chem. 2004 Jul 16;279(29):30402-9.
PubMed.
Recent research offers new clues into the pathogenesis of prion diseases
Glycation Involved in the Formation of Aberrant Prion Protein Isoform PrPSc
Mark E. Obrenovich and Vincent M. Monnier
Prion diseases comprise a group of neurodegenerative diseases, termed the transmissible spongiform encephalopathies (TSEs). Collectively these diseases are heterotypic, heterogenous, demonstrate species heterogeneity and have varied clinical presentations (1). Often, prion diseases are grouped with slow viral infections, as some forms of the disease share common features. The term slow viral diseases refer to a class of diseases that have a prolonged incubation period, which can range from months to years, and have a protracted, progressive clinical course (2). The term has nothing to do with the growth rate of any virus and no nucleic acid has been detected, to date, in the lesions associated with prion disease. Further, treatments to eradicate nucleic acid from purified preparations of infective material do nothing to destroy infectivity (3). Nevertheless, the proteinaceous infectious particles in the various prion diseases are thought to be similar, although the symptoms associated with the diseases forms may differ.
Environmental and genetic factors are known to be involved in the etiology of the disease, however the mechanism by which this process happens still is poorly understood. Some patients may present with a variety of symptoms, albeit the neuropathology of some prion diseases, such as kuru, Creutzfeldt-Jakob disease (CJD) as well as Gerstmann-Straüssler-Scheinker syndrome (GSS), are notably similar (4, 5) All the TSE are confined to the central nervous system and can have a dominant mode of genetic heritability, can be acquired or can arise sporadically, which is by far the most commonly noted etiology. Interestingly, in the new variant forms of CJD investigators have found increased infectious agent in the peripheral tissues (6). Some of the TSEs are amyloidogenic, however some are not, which contributes to the poor understanding of the etiology of the TSEs.
One mechanistic hypothesis is that the infectious form of the prion protein, which is resistant to denaturation by select means, can convert the normal form of the protein to the resistant form, and thus, the conversion rate gradually increases until eventually all the amplified protein is of the resistant isoform (7). Nevertheless, pathogenesis is believed to result largely from a conformational change in the folding of the native protein and is why these and other diseases became known as “conformational” diseases. This conformational change, which is common to all amyloid, has been described to occur in largely fibrillar native proteins but can also occur in globular proteins as well. When native proteins with a largely alpha-helical structure lose their original conformation and are converted into a predominantly beta-sheet form, they increase the propensity to form highly insoluble and fibrillar aggregates (8, 9, 10). These aberrantly folded isoforms are not readily turned over or cleared by conventional means, are not known to be immunogenic and tend to form deposits, which typify the cellular inclusions or plaques of amyloid fibrils that are characteristic hallmarks of all amyloid diseases (or amyloidoses) and the so-called conformational diseases. The secondary protein structures of pathogenic forms of prion protein and most soluble amyloid precursor proteins have substantial beta-pleated sheet structure, while extensive beta-pleated sheet structure occurs in all of the deposited fibrils and plaques in these “conformational diseases”(11). Of growing importance in understanding the mechanism of TSEs pathology is the protracted time course that many forms of TSEs take. Further, it also is very plausible that once proteins become glycated at their exposed lysine residues, clearance by the ubiquitin-proteasome system would be impaired (12).
Recently, we reported on findings that glycation, i.e. the nonenzymatic chemical reaction that occurs between reducing sugars or reactive aldehydes and proteins, predisposes to amyloid formation (13). While it is not surprising to find glycation present in protracted diseases, it is of immense importance to understand the role that glycation has in predisposing to amyloid formation. The elucidation of this pathogenic process could lead investigators to search for ways to inhibit the glycation reaction or enhance clearance of abnormally folded proteins, and thus prevent conformational diseases (14, 15). Indeed, similar non-enzymatic glycation processes, already found in many amyloid diseases, are now known to be involved in the processing of some TSEs. Thus, prion disease, which requires a prerequisite nucleation process for pathogenesis, may in fact begin with glycation. In that regard, we report a new finding from the Korean and American groups of Choi, Kim, Carp and colleagues, which points to the post-translational process of glycation as a key mechanism in the pathogenesis of the prion protein in select TSEs (16). The posttranslational modifications involved in the processing and conversion of the cellular prion protein PrPC into the pathogenic isoform PrPSc, are becoming more clear, nevertheless, these modifications themselves are poorly understood. What is clear is that the conversion of the prion protein results in structural changes that render the aberrant form resistant to proteases, particularly Proteinase-K (17). However, the temporal aspects of these modifications remain to be elucidated.
Although the Maillard reaction, and its AGEs, has been demonstrated in numerous neurodegenerative diseases (18, 19), this new research is the first to show that glycation plays a role in the post-translational processing of PrPSc. These are features commonly shared by all known, aberrantly folded, and pathogenic forms of prion proteins. The group reports that in animal and human TSEs, select lysine residues, and other basic amino acids, are subject to post-translational modification by immunoreactive advanced glyction endproducts (AGEs). These AGE modifications have been found at the N-terminus of PrPSc but not the PrPC isoform. When the aberrant form of the protein was digested with Proteinase K, a 90 amino acid N-terminal sequence was lost from the PrPSc and the AGE epitopes were lost as well. The site of AGE-modification was narrowed to within the 23-89 AA N-terminus of the prion protein. The investigators went on to design peptides of various lengths and mapped the exact location of the non-enzymatic glycation, which was between peptide 23-36 and involved terminal lysine residues, one of which was specifically modified by the AGE carboxymethyl lysine (CML). While their data suggests that the PrPC to PrPSc conversion occurs prior to the AGE modification, these results may only reflect the relative detection sensitivity between the two antibodies and are not necessarily a reflection of any temporal aspect of disease pathogenesis. These results are not mutually exclusive with previous work by Bouma and colleagues, who demonstrated that non-enzymatic glycation predisposes to amyloid formation. Further, these results do not exclude the possibility that protein glycation, which occurs over time normally in long-lived proteins, may occur as a direct result of ineffective turnover of the PrPSC isoform. Nevertheless, these results will need further investigation and a clarification of the role of glycation in the pathogenesis of conformational diseases.
References:
Gambetti P, Parchi P, Capellari S, Russo C, Tabaton M, Teller JK, Chen SG.
Mechanisms of phenotypic heterogeneity in prion, Alzheimer and other conformational diseases.
J Alzheimers Dis. 2001 Feb;3(1):87-95.
PubMed.
Nandi PK.
Protein conformation and disease.
Vet Res. 1996;27(4-5):373-82.
PubMed.
Sternbach G, Dibble CL, Varon J.
From Creutzfeldt-Jakob disease to the mad cow epidemic.
J Emerg Med. 1997 Sep-Oct;15(5):701-5.
PubMed.
Nandi PK.
Prions at the crossroads: the need to identify the active TSE agent.
Bioessays. 2004 May;26(5):469-73.
PubMed.
Stumpf MP, Krakauer DC.
Mapping the parameters of prion-induced neuropathology.
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10573-7.
PubMed.
Gambetti P, Kong Q, Zou W, Parchi P, Chen SG.
Sporadic and familial CJD: classification and characterisation.
Br Med Bull. 2003;66:213-39.
PubMed.
Salmona M, Morbin M, Massignan T, Colombo L, Mazzoleni G, Capobianco R, Diomede L, Thaler F, Mollica L, Musco G, Kourie JJ, Bugiani O, Sharma D, Inouye H, Kirschner DA, Forloni G, Tagliavini F.
Structural properties of Gerstmann-Straussler-Scheinker disease amyloid protein.
J Biol Chem. 2003 Nov 28;278(48):48146-53.
PubMed.
Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, Dearmond SJ, Prusiner SB.
Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans.
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15137-42.
PubMed.
Díaz-Nido J, Wandosell F, Avila J.
Glycosaminoglycans and beta-amyloid, prion and tau peptides in neurodegenerative diseases.
Peptides. 2002 Jul;23(7):1323-32.
PubMed.
Diaz-Avalos R, Long C, Fontano E, Balbirnie M, Grothe R, Eisenberg D, Caspar DL.
Cross-beta order and diversity in nanocrystals of an amyloid-forming peptide.
J Mol Biol. 2003 Jul 25;330(5):1165-75.
PubMed.
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG.
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
Science. 2003 Apr 18;300(5618):486-9.
PubMed.
Sipe JD, Cohen AS.
Review: history of the amyloid fibril.
J Struct Biol. 2000 Jun;130(2-3):88-98.
PubMed.
Nguyen JT, Inouye H, Baldwin MA, Fletterick RJ, Cohen FE, Prusiner SB, Kirschner DA.
X-ray diffraction of scrapie prion rods and PrP peptides.
J Mol Biol. 1995 Sep 29;252(4):412-22.
PubMed.
Bence NF, Sampat RM, Kopito RR.
Impairment of the ubiquitin-proteasome system by protein aggregation.
Science. 2001 May 25;292(5521):1552-5.
PubMed.
Bouma B, Kroon-Batenburg LM, Wu YP, Brünjes B, Posthuma G, Kranenburg O, de Groot PG, Voest EE, Gebbink MF.
Glycation induces formation of amyloid cross-beta structure in albumin.
J Biol Chem. 2003 Oct 24;278(43):41810-9.
PubMed.
Hirschfield GM, Hawkins PN.
Amyloidosis: new strategies for treatment.
Int J Biochem Cell Biol. 2003 Dec;35(12):1608-13.
PubMed.
Monnier VM.
Intervention against the Maillard reaction in vivo.
Arch Biochem Biophys. 2003 Nov 1;419(1):1-15.
PubMed.
Choi YG, Kim JI, Jeon YC, Park SJ, Choi EK, Rubenstein R, Kascsak RJ, Carp RI, Kim YS.
Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies.
J Biol Chem. 2004 Jul 16;279(29):30402-9.
PubMed.
Laurine E, Grégoire C, Fändrich M, Engemann S, Marchal S, Thion L, Mohr M, Monsarrat B, Michel B, Dobson CM, Wanker E, Erard M, Verdier JM.
Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease.
J Biol Chem. 2003 Dec 19;278(51):51770-8.
PubMed.
Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA.
Involvement of Maillard reactions in Alzheimer disease.
Neurotox Res. 2002 May;4(3):191-209.
PubMed.
Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A.
Advanced glycation end products contribute to amyloidosis in Alzheimer disease.
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4766-70.
PubMed.
Comments
Case Western Reserve University
Recent research offers new clues into the pathogenesis of prion diseases
Glycation Involved in the Formation of Aberrant Prion Protein Isoform PrPSc
Mark E. Obrenovich and Vincent M. Monnier
Prion diseases comprise a group of neurodegenerative diseases, termed the transmissible spongiform encephalopathies (TSEs). Collectively these diseases are heterotypic, heterogenous, demonstrate species heterogeneity and have varied clinical presentations (1). Often, prion diseases are grouped with slow viral infections, as some forms of the disease share common features. The term slow viral diseases refer to a class of diseases that have a prolonged incubation period, which can range from months to years, and have a protracted, progressive clinical course (2). The term has nothing to do with the growth rate of any virus and no nucleic acid has been detected, to date, in the lesions associated with prion disease. Further, treatments to eradicate nucleic acid from purified preparations of infective material do nothing to destroy infectivity (3). Nevertheless, the proteinaceous infectious particles in the various prion diseases are thought to be similar, although the symptoms associated with the diseases forms may differ.
Environmental and genetic factors are known to be involved in the etiology of the disease, however the mechanism by which this process happens still is poorly understood. Some patients may present with a variety of symptoms, albeit the neuropathology of some prion diseases, such as kuru, Creutzfeldt-Jakob disease (CJD) as well as Gerstmann-Straüssler-Scheinker syndrome (GSS), are notably similar (4, 5) All the TSE are confined to the central nervous system and can have a dominant mode of genetic heritability, can be acquired or can arise sporadically, which is by far the most commonly noted etiology. Interestingly, in the new variant forms of CJD investigators have found increased infectious agent in the peripheral tissues (6). Some of the TSEs are amyloidogenic, however some are not, which contributes to the poor understanding of the etiology of the TSEs.
One mechanistic hypothesis is that the infectious form of the prion protein, which is resistant to denaturation by select means, can convert the normal form of the protein to the resistant form, and thus, the conversion rate gradually increases until eventually all the amplified protein is of the resistant isoform (7). Nevertheless, pathogenesis is believed to result largely from a conformational change in the folding of the native protein and is why these and other diseases became known as “conformational” diseases. This conformational change, which is common to all amyloid, has been described to occur in largely fibrillar native proteins but can also occur in globular proteins as well. When native proteins with a largely alpha-helical structure lose their original conformation and are converted into a predominantly beta-sheet form, they increase the propensity to form highly insoluble and fibrillar aggregates (8, 9, 10). These aberrantly folded isoforms are not readily turned over or cleared by conventional means, are not known to be immunogenic and tend to form deposits, which typify the cellular inclusions or plaques of amyloid fibrils that are characteristic hallmarks of all amyloid diseases (or amyloidoses) and the so-called conformational diseases. The secondary protein structures of pathogenic forms of prion protein and most soluble amyloid precursor proteins have substantial beta-pleated sheet structure, while extensive beta-pleated sheet structure occurs in all of the deposited fibrils and plaques in these “conformational diseases”(11). Of growing importance in understanding the mechanism of TSEs pathology is the protracted time course that many forms of TSEs take. Further, it also is very plausible that once proteins become glycated at their exposed lysine residues, clearance by the ubiquitin-proteasome system would be impaired (12).
Recently, we reported on findings that glycation, i.e. the nonenzymatic chemical reaction that occurs between reducing sugars or reactive aldehydes and proteins, predisposes to amyloid formation (13). While it is not surprising to find glycation present in protracted diseases, it is of immense importance to understand the role that glycation has in predisposing to amyloid formation. The elucidation of this pathogenic process could lead investigators to search for ways to inhibit the glycation reaction or enhance clearance of abnormally folded proteins, and thus prevent conformational diseases (14, 15). Indeed, similar non-enzymatic glycation processes, already found in many amyloid diseases, are now known to be involved in the processing of some TSEs. Thus, prion disease, which requires a prerequisite nucleation process for pathogenesis, may in fact begin with glycation. In that regard, we report a new finding from the Korean and American groups of Choi, Kim, Carp and colleagues, which points to the post-translational process of glycation as a key mechanism in the pathogenesis of the prion protein in select TSEs (16). The posttranslational modifications involved in the processing and conversion of the cellular prion protein PrPC into the pathogenic isoform PrPSc, are becoming more clear, nevertheless, these modifications themselves are poorly understood. What is clear is that the conversion of the prion protein results in structural changes that render the aberrant form resistant to proteases, particularly Proteinase-K (17). However, the temporal aspects of these modifications remain to be elucidated.
Although the Maillard reaction, and its AGEs, has been demonstrated in numerous neurodegenerative diseases (18, 19), this new research is the first to show that glycation plays a role in the post-translational processing of PrPSc. These are features commonly shared by all known, aberrantly folded, and pathogenic forms of prion proteins. The group reports that in animal and human TSEs, select lysine residues, and other basic amino acids, are subject to post-translational modification by immunoreactive advanced glyction endproducts (AGEs). These AGE modifications have been found at the N-terminus of PrPSc but not the PrPC isoform. When the aberrant form of the protein was digested with Proteinase K, a 90 amino acid N-terminal sequence was lost from the PrPSc and the AGE epitopes were lost as well. The site of AGE-modification was narrowed to within the 23-89 AA N-terminus of the prion protein. The investigators went on to design peptides of various lengths and mapped the exact location of the non-enzymatic glycation, which was between peptide 23-36 and involved terminal lysine residues, one of which was specifically modified by the AGE carboxymethyl lysine (CML). While their data suggests that the PrPC to PrPSc conversion occurs prior to the AGE modification, these results may only reflect the relative detection sensitivity between the two antibodies and are not necessarily a reflection of any temporal aspect of disease pathogenesis. These results are not mutually exclusive with previous work by Bouma and colleagues, who demonstrated that non-enzymatic glycation predisposes to amyloid formation. Further, these results do not exclude the possibility that protein glycation, which occurs over time normally in long-lived proteins, may occur as a direct result of ineffective turnover of the PrPSC isoform. Nevertheless, these results will need further investigation and a clarification of the role of glycation in the pathogenesis of conformational diseases.
References:
Gambetti P, Parchi P, Capellari S, Russo C, Tabaton M, Teller JK, Chen SG. Mechanisms of phenotypic heterogeneity in prion, Alzheimer and other conformational diseases. J Alzheimers Dis. 2001 Feb;3(1):87-95. PubMed.
Nandi PK. Protein conformation and disease. Vet Res. 1996;27(4-5):373-82. PubMed.
Sternbach G, Dibble CL, Varon J. From Creutzfeldt-Jakob disease to the mad cow epidemic. J Emerg Med. 1997 Sep-Oct;15(5):701-5. PubMed.
Nandi PK. Prions at the crossroads: the need to identify the active TSE agent. Bioessays. 2004 May;26(5):469-73. PubMed.
Stumpf MP, Krakauer DC. Mapping the parameters of prion-induced neuropathology. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10573-7. PubMed.
Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull. 2003;66:213-39. PubMed.
Salmona M, Morbin M, Massignan T, Colombo L, Mazzoleni G, Capobianco R, Diomede L, Thaler F, Mollica L, Musco G, Kourie JJ, Bugiani O, Sharma D, Inouye H, Kirschner DA, Forloni G, Tagliavini F. Structural properties of Gerstmann-Straussler-Scheinker disease amyloid protein. J Biol Chem. 2003 Nov 28;278(48):48146-53. PubMed.
Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, Dearmond SJ, Prusiner SB. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15137-42. PubMed.
Díaz-Nido J, Wandosell F, Avila J. Glycosaminoglycans and beta-amyloid, prion and tau peptides in neurodegenerative diseases. Peptides. 2002 Jul;23(7):1323-32. PubMed.
Diaz-Avalos R, Long C, Fontano E, Balbirnie M, Grothe R, Eisenberg D, Caspar DL. Cross-beta order and diversity in nanocrystals of an amyloid-forming peptide. J Mol Biol. 2003 Jul 25;330(5):1165-75. PubMed.
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003 Apr 18;300(5618):486-9. PubMed.
Sipe JD, Cohen AS. Review: history of the amyloid fibril. J Struct Biol. 2000 Jun;130(2-3):88-98. PubMed.
Nguyen JT, Inouye H, Baldwin MA, Fletterick RJ, Cohen FE, Prusiner SB, Kirschner DA. X-ray diffraction of scrapie prion rods and PrP peptides. J Mol Biol. 1995 Sep 29;252(4):412-22. PubMed.
Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001 May 25;292(5521):1552-5. PubMed.
Bouma B, Kroon-Batenburg LM, Wu YP, Brünjes B, Posthuma G, Kranenburg O, de Groot PG, Voest EE, Gebbink MF. Glycation induces formation of amyloid cross-beta structure in albumin. J Biol Chem. 2003 Oct 24;278(43):41810-9. PubMed.
Hirschfield GM, Hawkins PN. Amyloidosis: new strategies for treatment. Int J Biochem Cell Biol. 2003 Dec;35(12):1608-13. PubMed.
Monnier VM. Intervention against the Maillard reaction in vivo. Arch Biochem Biophys. 2003 Nov 1;419(1):1-15. PubMed.
Choi YG, Kim JI, Jeon YC, Park SJ, Choi EK, Rubenstein R, Kascsak RJ, Carp RI, Kim YS. Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies. J Biol Chem. 2004 Jul 16;279(29):30402-9. PubMed.
Laurine E, Grégoire C, Fändrich M, Engemann S, Marchal S, Thion L, Mohr M, Monsarrat B, Michel B, Dobson CM, Wanker E, Erard M, Verdier JM. Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease. J Biol Chem. 2003 Dec 19;278(51):51770-8. PubMed.
Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA. Involvement of Maillard reactions in Alzheimer disease. Neurotox Res. 2002 May;4(3):191-209. PubMed.
Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4766-70. PubMed.
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