Huntington's disease is a neurological disorder caused by the expansion of a polyglutamine tract in the protein huntingtin. Several other neurological diseases also result from the expansion of polyglutamine regions in different proteins. Despite intense efforts, no definitive biochemical or physiological role for huntingtin has been described, nor has a function been assigned to the polyglutamine region in unaffected individuals. This article presents the hypothesis that polyglutamine expansions within huntingtin and other polyglutamine proteins provide a function in and of themselves. Incorporating multiple glutamine residues into a protein during synthesis, and releasing them during protein turnover, may represent a means of minimizing interruptions in brain levels of glutamine and glutamate during periods of malnutrition. The number and variety of different proteins containing polyglutamine expansions can be interpreted as a series of evolutionary “experiments” toward a nontoxic form for glutamine storage.
Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. 2004. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature431:805–810.
3.
Barnes GT, Duyao MP, Ambrose CM, McNeil S, Persichetti F, Srinidhi J, and others. 1994. Mouse Huntington's disease gene homolog (Hdh). Som Cell Mol Genet20:87–97.
4.
Baxendale S, Abdulla S, Elgar G, Bucks D, Berks M, Micklem G, and others. 1995. Comparative sequence analysis of the human and pufferfish Huntington's disease genes. Nat Genet10:67–76.
5.
Brusilow SW. 2002. Hyperammonemic encephalopathy. Medicine (Baltimore)81:240–249.
6.
Clabough EB, Zeitlin SO. 2006. Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro. Hum Mol Genet15:607–623.
7.
Cooper AJL. 1988. Glutamine synthetase. In: Kvamme E, editor. Glutamine and glutamate in mammals. Boca Raton, FL: CRC. p. 7–31.
8.
Cooper AJL. 2001. Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity. Ment Retard Dev Disabil Res Rev7:280–286.
9.
Cooper AJL, Blass JP. 2006. Trinucleotide-expansion diseases. New York: Kluwer Academic/Plenum.
10.
Djian P, Hancock JM, Chana HS. 1996. Codon repeats in genes associated with human diseases: fewer repeats in the genes of nonhuman primates and nucleotide substitutions concentrated at the sites of reiteration. Proc Natl Acad Sci U S A93:417–421.
11.
Hawkins RA, O'Kane RL, Simpson IA, Vina JR. 2006. Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr136:218S–26S.
12.
Heath PR, Shaw PJ. 2002. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve26:438–458.
13.
Hertz L, Dringen R, Schaousboe A, Robinson SR. 1999. Astrocytes: glutamate producers for neurons. J Neurosci Res57:417–428.
14.
Karlovich DA, John RM, Ramirez L, Stainier DYR, Meyers RM. 1998. Characterization of the Huntington's disease (HD) gene homolog in the zebrafish Danio rerio. Gene217:117–125.
15.
Kikuno R, Nagase T, Nakayama M, Koga H, Okazaki N, Nakajima D, Ohara O. 2004. HUGE: a database for human KIAA proteins, a 2004 update integrating HUGEppi and ROUGE. Nucleic Acid Res32:D502–D504.
16.
Laake JH, Slyngstad TA, Haug F-MS, Ottersen OP. 1995. Glutamine from glial cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. J Neurochem65:871–881.
17.
Li Z, Karlovich CA, Fish MP, Scott MP, Myers RM. 1999. A putative Drosophila homolog of the Huntington's disease gene. Hum Mol Genet8:1807–1815.
Martinez-Hernandez A, Bell KP, Norenberg MD. 1977. Glutamine synthetase: glial localization in brain. Science195:1356–1358.
20.
Matsuyama N, Hadano S, Onoe K, Osuga H, Showguchi-Miyata J, Gondo Y, Ikeda J-E. 2000. Identification and characterization of the miniature pig Huntington's disease gene homolog: evidence for conservation and polymorphism in the CAG triplet repeat. Genomics69:72–85.
21.
Nasir J, Floresco SB, O'Kusky JR, Diewart VM, Richman JM, Zeisler J, and others. 1995. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell81:811–823.
22.
Pearson WR, Lipman DJ. 1988. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A85:2444–2448.
23.
Petroff OA, Rothman DL, Behar KL, Hyder F, Mattson RH. 1999. Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure8:120–127.
24.
Pow DV, Robinson SR. 1994. Glutamate in some retinal neurons is derived solely from glia. Neuroscience60:355–366.
25.
Qin Z, Gu Z. 2004. Huntingtin processing in pathogenesis of Huntington disease. Acta Pharmacol Sin25:1243–1249.
26.
Rubinsztein DC, Amos W, Leggo J, Goodburn S, Ramesar RS, Old J, and others. 1994. Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence. Nat Genet7:525–530.
27.
Schmitt I, Bachner D, Megow D, Henklein P, Hameister H, Epplen JT, Riess O. 1995. Expression of the Huntington disease gene in rodents: cloning the rat homologue and evidence for downregulation in non-neuronal tissues during development. Hum Mol Genet4:1173–1182.
28.
Schubert F, Gallinat J, Seifert F, Rinneberg H. 2004. Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla. Neuroimage21:1762–1771.
29.
Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, and others. 2005. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet14:2871–2880.
30.
Yudkoff M.1997. Brain metabolism of branched-chain amino acids. Glia21:92–98.
31.
Yudkoff M, Daikhin Y, Nissim I, Horyn O, Luhovyy B, Lazarow A, and others. 2005. Brain amino acid requirements and toxicity: the example of leucine. J Nutr135:1531S–8S.
32.
Yudkoff M, Zaleska MM, Nissim I, Nelson D, Erecinska M. 1989. Neuronal glutamine utilization: pathways of nitrogen transfer studies with [15N] glutamine. J Neurochem53:632–640.
33.
Zeitlin S, Liu J-P, Chapman DL, Papaioannou VE, Efstratiadis A, 1995. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat Genet11:155–163.
34.
Zhou H, Cao F, Wang Z, Yu ZX, Nguyen HP, Evans J, and others. 2003. Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J Cell Biol163:109–118.
