Increased levels of γ‐glutamylamines in Huntington disease CSF

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Journal of Neurochemistry (Impact Factor: 4.28). 08/2008; 106(1):37-44. DOI: 10.1111/j.1471-4159.2008.05350.x
Source: PubMed


Transglutaminases (TGases) catalyze several reactions with protein substrates, including formation of gamma-glutamyl-epsilon-lysine cross-links and gamma-glutamylpolyamine residues. The resulting gamma-glutamylamines are excised intact during proteolysis. TGase activity is altered in several diseases, highlighting the importance of in situ enzymatic determinations. Previous work showed that TGase activity (as measured by an in vitro assay) and free gamma-glutamyl-epsilon-lysine levels are elevated in Huntington disease (HD) and that gamma-glutamyl-epsilon-lysine is increased in HD CSF. Although free gamma-glutamyl-epsilon-lysine was used in these studies as an index of in situ TGase activity, gamma-glutamylpolyamines may also be diagnostic. We have devised methods for the simultaneous determination of four gamma-glutamylamines in CSF: gamma-glutamyl-epsilon-lysine, gamma-glutamylspermidine, gamma-glutamylputrescine, and bis-gamma-glutamylputrescine and showed that all are present in normal human CSF at concentrations of approximately 150, 670, 40, and 240 nM, respectively. The high gamma-glutamylspermidine/gamma-glutamylputrescine and gamma-glutamylspermidine/bis-gamma-glutamylputrescine ratios presumably reflect in part the large spermidine to putrescine mole ratio in human brain. We also showed that all four gamma-glutamylamines are elevated in HD CSF. Our findings support the hypotheses that (i) gamma-glutamylpolyamines are reflective of TGase activity in human brain, (ii) polyamination is an important post-translational modification of brain proteins, and (iii) TGase-catalyzed modification of proteins is increased in HD brain.

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Available from: Arthur J L Cooper
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    • "Alternatively, TG2 is involved in autophagosome maturation, and SPD-induced autophagy is able to promote longevity of yeast (D'Eletto et al. 2009; Morselli et al. 2009). In addition, TG2 may contribute to neurodegeneration through cross-linking or polyamination of the brain proteins such as amyloid-β, tau, α-synuclein, and huntingtin (Jeitner et al. 2008, 2009, 2013). In particular , γ-glutamyl polyamines in human CSF are elevated in CSF from Huntington disease patients. "
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    • "Similarly, the presence of TG crosslinked a-synuclein in substantia nigra dopaminergic neurons of Parkinson's disease patients has been demonstrated (Andringa et al. 2004). The fact that increased levels of the c-glutamyl-e-lysine crosslink as well as bis-c-glutamylpolyamine are found in the affected tissue and in the cerebrospinal fluid (Zainelli et al. 2003; Nemes et al. 2004; Jeitner et al. 2008) indicates that TG2 and possibly other TG isozymes extensively modify proteins and possibly also diseasespecific protein aggregates. Mouse models have substantiated a direct role of TG2 in the pathogenesis of Huntington's and other neurodegenerative diseases albeit the mechanisms involved being somewhat unexpected. "
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    • "In addition to these experimental findings, it has been shown that TGs and transglutaminase-catalyzed cross-links colocalize with pathological lesions in Alzheimer's disease brain [34–36]. Interestingly, a recent work showed the presence of bis γ-glutamyl putrescine in human CSF, which was increased in Huntington's disease (HD) CSF [37]. These are important experimental data which demonstrate that protein/peptides cross-links and protein/peptides cross-linking by polyamines do indeed occur in brain, and that these transglutaminase-catalyzed reaction products are increased in AD and HD brains. "
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