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. 1998 Jan;21(1):25–30. doi: 10.1007/s11357-998-0004-x

Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions?

Arthur J L Cooper 1,2,4,8,✉, K-F Rex Sheu 2,4, James R Burke 5,7, Osamu Onodera 5,7, Warren J Strittmatter 5,6,7, Allen D Roses 5,6,7, John P Blass 2,4,3
PMCID: PMC3455770  PMID: 23604331

Abstract

At least seven adult-onset neurodegenerative diseases, including Huntington’s disease (HD), are caused by genes containing expanded CAG triplets within their coding regions. The expanded CAG repeats give rise to extended stretches of polyglutamines (Qn) in the proteins expressed by the affected genes. Generally, n ≥40 in affected individuals and ≤36 in clinically unaffected individuals. The expansion has been proposed to confer a “toxic gain of function” to the mutated protein. Poly-Q domains have recently been shown to be excellent substrates of tissue transglutaminase. We investigated the effects of expression of glutathione S-transferase constructs containing poly-Q inserts of various lengths (GSTQn where n = 0, 10, 62 or 81) on the activity of some key metabolic enzymes in the host Escherischia coil-an organism not known to have transglutaminase activity. E. coil carrying the GSTQ62 construct exhibited statistically significant decreases in the specific activities of α-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC). Previous work has shown that KGDHC and PDHC activities are reduced in the brains of Alzheimer’s disease (AD) patients. Our results suggest that KGDHC and PDHC may be particularly susceptible to the effects of a number of disparate insults, including those associated with AD and HD.

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References

  • 1.Burke J.R., Enghild J.J., Martin M.E., Jou Y.-S., Myers R.M., Roses A.D., Vance J.M., Strittmatter W.J. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 1996;2:347–350. doi: 10.1038/nm0396-347. [DOI] [PubMed] [Google Scholar]
  • 2.Koshy B., Matilla T., Burright E.N., Merry D.E., Fischbeck K.H., Orr H.T., Zoghbi H.Y. Spinocerebellar ataxia type-1 and spinocerebellar muscular atrophy gene products interact with glyceraldehyde-phosphate dehydrogenase. Human Mol. Gen. 1996;5:1311–1318. doi: 10.1093/hmg/5.9.1311. [DOI] [PubMed] [Google Scholar]
  • 3.Mangiarini L., Sathasivan K., Seller M., Cozens B., Harper A., Hetherington C., Lawton M., Trottier Y., Lehrach H., Davies S.W., Bates G.P. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87:493–506. doi: 10.1016/S0092-8674(00)81369-0. [DOI] [PubMed] [Google Scholar]
  • 4.Imbert G., Saudou F., Yvert G., Devys D., Trottier Y., Gamier J.M., Weber C., Mandel J.L., Cancel G., Abbas N., Durr A., Didierjean O., Stevanini G., Agid Y., Brice A. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with sensitivity to expanded CAG/glutamine repeats. Nature Gen. 1996;14:285–291. doi: 10.1038/ng1196-285. [DOI] [PubMed] [Google Scholar]
  • 5.Lindblad K., Savontaus M.L., Stevanin G., Holmberg M., Digre K., Zander C., Ehrsson H., David G., Benomar A., Nikoskelainen E., Trottier Y., Holmgren G., Ptacek L.J., Anttinen A., Brice A., Schalling M. An expanded CAG repeat sequence in spinocerebellar ataxia type 7. Genome Res. 1996;6:965–971. doi: 10.1101/gr.6.10.965. [DOI] [PubMed] [Google Scholar]
  • 6.Cooper AJL, Sheu K-FR, Onodera O, Burke JR, Stritmatter WJ, Roses AD and Blass JP. Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by poly-Q domains of pathological length. Proc. Natl. Acad. Sci. 94: 12604–12609, 1997. [DOI] [PMC free article] [PubMed]
  • 7.Green H. Human genetic diseases due to codon reiteration: Relationship to an evolutionary mechanism. Cell. 1993;74:955–956. doi: 10.1016/0092-8674(93)90718-6. [DOI] [PubMed] [Google Scholar]
  • 8.Ikeda H., Yamaguchi M., Sugai S., Aze Y., Narumia S., Kakizuka A. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nature Gen. 1996;13:196–202. doi: 10.1038/ng0696-196. [DOI] [PubMed] [Google Scholar]
  • 9.Kahlem P, Terré C, Green H and Djian P. Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: Relevance to diseases of the nervous system. Proc. Natl. Acad. Sci. U. S. A. 93: 14580–14585, 1996. [DOI] [PMC free article] [PubMed]
  • 10.Cooper A.J.L., Sheu K.-F., Onodera O., Burke J.R., Strittmatter W. J., Roses A.D., Blass J.P. Polyglutamine domains are substrates of tissue transglutaminase. Does transglutaminase play a role in expanded CAG/poly-Q repeat neurodegenerative diseases? J. Neurochem. 1997;69:431–434. doi: 10.1046/j.1471-4159.1997.69010431.x. [DOI] [PubMed] [Google Scholar]
  • 11.Stott K., Blackburn J.M., Butler P.J.G., Perutz M. Incorporation of glutamine repeats makes protein oligomerize: Implications for neurodegerative diseases. Proc. Natl. Acad. Sci. U. S. A. 1995;92:6509–6513. doi: 10.1073/pnas.92.14.6509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Chung S.I. Comparative studies of tissue transglutaminase and factor XIII. Ann. N. Y. Acad. Sci. 1972;202:240–255. doi: 10.1111/j.1749-6632.1972.tb16338.x. [DOI] [PubMed] [Google Scholar]
  • 13.Onodera O., Roses A., Tsuji S., Vance J.M., Strittmatter W.J., Burke J.R. Toxicity of expanded poly-glutamine-domain proteins in Escherischia coli. FEBS Lett. 1996;399:135–139. doi: 10.1016/S0014-5793(96)01301-4. [DOI] [PubMed] [Google Scholar]
  • 14.Folk J.E., Cole P.W. Transglutaminase: Mechanistic features of the active site as determined by kinetic and inhibitor studies. Biochim. Biophys. Chim. Acta. 1966;122:244–264. doi: 10.1016/0926-6593(66)90066-x. [DOI] [PubMed] [Google Scholar]
  • 15.Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951;193:265–275. [PubMed] [Google Scholar]
  • 16.Gerber U., Jucknischke U., Putzien S., Fuchsbauer H.-L. A rapid and simple method for the purification of transglutaminase from Streptoverticullum mobaraense. Biochem. J. 1994;299:825–829. doi: 10.1042/bj2990825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Ruiz-Herrera J., Iranzo M., Elorza M.V., Sentanddreu R., Mormeneo S. Involvement of transglutaminase in the formation of covalent cross-links in the cell wall of Candida albicans. Arch. Microbiol. 1995;164:186–193. doi: 10.1007/s002030050253. [DOI] [PubMed] [Google Scholar]
  • 18.Blass J.P., Sheu R.-F., Cederbaum J.M. Energy metabolism in disorders of the nervous system. Rev. Neurol. (Paris) 1988;144:543–563. [PubMed] [Google Scholar]
  • 19.Beal M.F. Aging, energy metabolism, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 1995;38:357–366. doi: 10.1002/ana.410380304. [DOI] [PubMed] [Google Scholar]
  • 20.Blass J.P. Energy/glucose metabolism in neurodegenerative diseases. In: Wasco W., Tanzi R.E., editors. Molecular Mechanisms of Dementia. NY: Humana Press; 1997. pp. 91–101. [Google Scholar]
  • 21.Sorbi S., Bird E.D., Blass J.P. Decreased pyruvate dehydrogenase complex activity in Huntintgton and Alzheimer brain. Ann. Neurol. 1983;13:72–78. doi: 10.1002/ana.410130116. [DOI] [PubMed] [Google Scholar]
  • 22.Mizuno Y., Ikebe S., Hattori N., Nakagawa-Hattori Y., Mochizuki H., Tanaka M., Ozawa T. Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim. Biophys. Acta. 1995;1271:265–274. doi: 10.1016/0925-4439(95)00038-6. [DOI] [PubMed] [Google Scholar]
  • 23.Gibson G.E., Sheu K.-F., Blass J.P., Baker A., Carlson K.C., Harding B., Perion P. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch. Neurol. 1988;45:841–845. doi: 10.1001/archneur.1988.00520320022009. [DOI] [PubMed] [Google Scholar]
  • 24.Butterworth R.F., Besnard A.M. Thiamine-dependent enzyme changes in the temporal cortex of patients with Alzheimer’s disease. Metab. Brain. Dis. 1990;5:179–184. doi: 10.1007/BF00997071. [DOI] [PubMed] [Google Scholar]
  • 25.Mastrogiacomo F., Lindsay J.G., Bettendorf L., Rice J., Kish S.J. Brian protein and α-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. Ann. Neurol. 1996;39:592–598. doi: 10.1002/ana.410390508. [DOI] [PubMed] [Google Scholar]
  • 26.Sheu K.-F., Cooper A.J.L., Koike K., Koike M., Lindsay J.G., Blass J.P. Abnormality of the α-ketoglutarate dehydrogenase complex in fibroblasts from familial Alzheimer’s disease. Ann. Neurol. 1994;35:312–318. doi: 10.1002/ana.410350311. [DOI] [PubMed] [Google Scholar]
  • 27.Blass J.P., Sheu K.-F., Piacentini S., Sorbi S. Inherent abnormalities in oxidative metabolism in Alzheimer disease: Interaction with vascular abnormalities. Ann. NY Acad. Sci. 1997;826:382–385. doi: 10.1111/j.1749-6632.1997.tb48488.x. [DOI] [PubMed] [Google Scholar]
  • 28.Mastrogiacomo F., Kish S.J. Cerebellar α-ketoglutarate dehydrogenase activity is reduced in spinocerebellar ataxia type I. Ann. Neurol. 1994;35:624–626. doi: 10.1002/ana.410350519. [DOI] [PubMed] [Google Scholar]
  • 29.Mizuno Y., Matuda S., Yoshino H., Mori H., Hattori N., Ikebe S. An immunohistochemical study of α-ketoglutarate dehydrogenase complex in Parkinson’s disease. Ann. Neurol. 1994;35:204–210. doi: 10.1002/ana.410350212. [DOI] [PubMed] [Google Scholar]
  • 30.Sorbi S., Piacentini, Fani C., Tonini S., Marini P., Amaducci L. Abnormalities of mitochondrial enzymes in hereditary ataxias. Acta Neurol. Scand. 1989;80:103–110. doi: 10.1111/j.1600-0404.1989.tb03849.x. [DOI] [PubMed] [Google Scholar]

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