Energy dysfunction in Huntington's disease: Insights from PGC-1α, AMPK, and CKB

Cellular and Molecular Life Sciences

Volumn 69, Issue 24, 2012, Pages 4107-4120

  Ju, Tz Chuen ^a   Lin, Yow Sien ^a   Chern, Yijuang ^a  

^a INSTITUTE OF BIOMEDICAL SCIENCES   (Taiwan)

Author keywords

AMP activated protein kinase; Brain type creatine kinase; Huntington's disease; Peroxisome proliferator activated receptor (PPAR) coactivator 1 ; Polyglutamine

Indexed keywords

CREATINE; CREATINE KINASE; CREATINE KINASE B; CREATINE PHOSPHATE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; UNCLASSIFIED DRUG;

CELL METABOLISM; CELL SURVIVAL; DIET SUPPLEMENTATION; DOSE RESPONSE; DRUG MEGADOSE; ENERGY METABOLISM; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME REGULATION; HUMAN; HUNTINGTON CHOREA; MOLECULAR PATHOLOGY; NONHUMAN; PARKINSON DISEASE; PROTEIN FUNCTION; REVIEW;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; CREATINE; CREATINE KINASE, BB FORM; ENERGY METABOLISM; HEAT-SHOCK PROTEINS; HUMANS; HUNTINGTON DISEASE; MICE; MODELS, BIOLOGICAL; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 84870698291     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-012-1025-2     Document Type: Review

References (191)

1. Martin JB, Gusella JF (1986) Huntington's disease. Pathogenesis and management. N Engl J Med 315:1267-1276
2. The Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971-983
3. Landles C, Bates GP (2004)Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep 5:958-963
4. Buckley NJ, Johnson R, Zuccato C, Bithell A, Cattaneo E (2010) The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease. Neurobiol Dis 39:28-39
5. Li H, Li SH, Yu ZX, Shelbourne P, Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. J Neurosci 21:8473-8481
6. Lin YS, Chen CM, Soong BW, Wu YR, Chen HM, Yeh WY, Wu DR, Lin YJ, Poon PW, Cheng ML, Wang CH, Chern Y (2011) Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease. J Clin Invest 121:1519-1523
7. Chiang MC, Chen HM, Lee YH, Chang HH, Wu YC, Soong BW, Chen CM, Wu YR, Liu CS, Niu DM, Wu JY, Chen YT, Chern Y (2007) Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease. Hum Mol Genet 16:483-498
8. Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS (2001) Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice. J Neurophysiol 86:2667-2677
9. Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, Singaraja R, Kazemi-Esfarjani P, Devon R, Kim SU, Bredesen DE, Tufaro F, Hayden MR (1998) Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet 18:150-154
10. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44:559-577
11. Borrell-Pages M, Zala D, Humbert S, Saudou F (2006) Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci 63:2642-2660
12. Oliveira JM (2010) Nature and cause of mitochondrial dysfunction in Huntington's disease: focusing on huntingtin and the striatum. J Neurochem 114:1-12
13. Subramaniam S, Snyder SH (2011) Huntington's disease is a disorder of the corpus striatum: focus on Rhes (Ras homologue enriched in the striatum). Neuropharmacology 60:1187-1192
14. Khoshnan A, Patterson PH (2011) The role of IkappaB kinase complex in the neurobiology of Huntington's disease. Neurobiol Dis 43:305-311
15. Crook ZR, Housman D (2011) Huntington's disease: can mice lead the way to treatment? Neuron 69:423-435
16. Ross CA, Tabrizi SJ (2011) Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83-98
17. Pratley RE, Salbe AD, Ravussin E, Caviness JN (2000)Higher sedentary energy expenditure in patients with Huntington's disease. Ann Neurol 47:64-70
18. Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed CR (1999) Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 48:649-651
19. Josefsen K, Nielsen MD, Jorgensen KH, Bock T, Norremolle A, Sorensen SA, Naver B, Hasholt L (2008) Impaired glucose tolerance in the R6/1 transgenic mouse model of Huntington's disease. J Neuroendocrinol 20:165-172
20. Trushina E, Singh RD, Dyer RB, Cao S, Shah VH, Parton RG, Pagano RE, McMurray CT (2006) Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo. Hum Mol Genet 15:3578-3591
21. ValenzaM,Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, StrandA, TarditiA,Woodman B, Racchi M,Mariotti C, Di Donato S, Corsini A, Bates G, Pruss R, Olson JM, Sipione S, Tartari M, Cattaneo E (2005)Dysfunction of the cholesterol biosynthetic pathway in Huntington's disease. J Neurosci 25:9932-9939
22. Valenza M, Carroll JB, Leoni V, Bertram LN, Bjorkhem I, Singaraja RR, Di Donato S, Lutjohann D, Hayden MR, Cattaneo E (2007) Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation. Hum Mol Genet 16:2187-2198
23. Morton AJ, Lagan MA, Skepper JN, Dunnett SB (2000)Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation. J Neurocytol 29:679-702
24. Karasinska JM, Hayden MR (2011) Cholesterol metabolism in Huntington disease. Nat Rev Neurol 7:561-572
25. Chiang MC, Chen HM, Lai HL, Chen HW, Chou SY, Chen CM, Tsai FJ, Chern Y (2009)The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system. Hum Mol Genet 18:2929-2942
26. Podolsky S, Leopold NA, Sax DS (1972) Increased frequency of diabetes mellitus in patients with Huntington's chorea. Lancet 1:1356-1358
27. Squitieri F, Cannella M, Sgarbi G, Maglione V, Falleni A, Lenzi P, Baracca A, Cislaghi G, Saft C, Ragona G, Russo MA, Thompson LM, Solaini G, Fornai F (2006) Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech Ageing Dev 127:217-220
28. Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci 28:2783-2792
29. Almeida S, Sarmento-Ribeiro AB, Januario C, Rego AC, Oliveira CR (2008) Evidence of apoptosis and mitochondrial abnormalities in peripheral blood cells of Huntington's disease patients. Biochem Biophys Res Commun 374:599-603
30. Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci 5:731-736
31. Panov AV, Burke JR, Strittmatter WJ, Greenamyre JT (2003) In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease. Arch Biochem Biophys 410:1-6
32. Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 281:34785-34795
33. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17:377-382
34. Wang H, Lim PJ, Karbowski M, Monteiro MJ (2009)Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18:737-752
35. Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol 41:646-653
36. Gu M, Gash MT, Mann VM, Javoy-Agid F, Cooper JM, Schapira AH (1996)Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 39:385-389
37. Benchoua A, Trioulier Y, Zala D, Gaillard MC, Lefort N, Dufour N, Saudou F, Elalouf JM, Hirsch E, Hantraye P, Deglon N, Brouillet E (2006) Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol Biol Cell 17:1652-1663
38. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF (2002) Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci 22:1592-1599
39. Fontaine MA, Geddes JW, Banks A, Butterfield DA (2000)Effect of exogenous and endogenous antioxidants on 3-nitropionic acid-induced in vivo oxidative stress and striatal lesions: insights into Huntington's disease. J Neurochem 75:1709-1715
40. Stack EC, Matson WR, Ferrante RJ (2008) Evidence of oxidant damage in Huntington's disease: translational strategies using antioxidants. Ann N Y Acad Sci 1147:79-92
41. Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF (2001) Lipoic acid improves survival in transgenic mouse models of Huntington's disease. Neuroreport 12:3371-3373
42. Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC (2002) Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci USA 99:10671-10676
43. Fernandes HB, Baimbridge KG, Church J, Hayden MR, Raymond LA (2007) Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington's disease. J Neurosci 27:13614-13623
44. Ju TC, Chen HM, Lin JT, Chang CP, Chang WC, Kang JJ, Sun CP, Tao MH, Tu PH, Chang C, Dickson DW, Chern Y (2011) Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease. J Cell Biol 194:209-227
45. Bossy-Wetzel E, Petrilli A, Knott AB (2008) Mutant huntingtin and mitochondrial dysfunction. Trends Neurosci 31:609-616
46. Li XJ, Orr AL, Li S (2010) Impaired mitochondrial trafficking in Huntington's disease. Biochim Biophys Acta 1802:62-65
47. Chang DT, Rintoul GL, Pandipati S, Reynolds IJ (2006) Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol Dis 22:388-400
48. Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson EN (2000)Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo. J Biol Chem 275:4545-4548
49. Huss JM, Torra IP, Staels B, Giguere V, Kelly DP (2004)Estrogen-related receptor alpha directs peroxisome proliferatoractivated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 24:9079-9091
50. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115-124
51. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829-839
52. Huss JM, Kopp RP, Kelly DP (2002) Peroxisome proliferatoractivated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptoralpha and-gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 277:40265-40274
53. Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA (2004)Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 18:157-169
54. Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649-688
55. Southgate RJ, Bruce CR, Carey AL, Steinberg GR, Walder K, Monks R, Watt MJ, Hawley JA, Birnbaum MJ, Febbraio MA (2005)PGC-1alpha gene expression is down-regulated by Aktmediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J 19:2072-2074
56. McGee SL, Hargreaves M (2004)Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes 53:1208-1214
57. Oberkofler H, Schraml E, Krempler F, Patsch W (2004)Restoration of sterol-regulatory-element-binding protein-1c gene expression in HepG2 cells by peroxisome-proliferator-activated receptor-gamma co-activator-1alpha. Biochem J 381:357-363
58. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM(2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131-138
59. Lelliott C, Vidal-Puig AJ (2004)Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int J Obes Relat Metab Disord 28(Suppl 4):S22-S28
60. Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R, Evans RM, Olefsky J, Montminy M (2004)PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med 10:530-534
61. Nemoto S, Fergusson MM, Finkel T (2005)SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem 280:16456-16460
62. Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMPactivated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104:12017-12022
63. Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S, Mootha VK, Lowell BB, Spiegelman BM (2001) Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell 8:971-982
64. Teyssier C, Ma H, Emter R, Kralli A, Stallcup MR (2005)Activation of nuclear receptor coactivator PGC-1alpha by arginine methylation. Genes Dev 19:1466-1473
65. Rytinki MM, Palvimo JJ (2009)SUMOylation attenuates the function of PGC-1alpha. J Biol Chem 284:26184-26193
66. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59-69
67. Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR (2006) Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab 4:349-362
68. Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, CannellaM, Sassone J, Ciammola A, Squitieri F, Beal MF (2009)Impaired PGC-1alpha function in muscle in Huntington's disease. Hum Mol Genet 18:3048-3065
69. Xiang Z, Valenza M, Cui L, Leoni V, Jeong HK, Brilli E, Zhang J, Peng Q, Duan W, Reeves SA, Cattaneo E, Krainc D (2011) Peroxisome-proliferator-activated receptor gamma coactivator 1 alpha contributes to dysmyelination in experimental models of Huntington's disease. J Neurosci 31:9544-9553
70. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005)PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3:e101
71. Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jager S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM (2004)Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119:121-135
72. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397-408
73. Chiang MC, Chern Y, Juo CG (2011) The dysfunction of hepatic transcriptional factors in mice with Huntington's Disease. Biochim Biophys Acta 1812:1111-1120
74. Chiang MC, Chern Y, Huang RN (2012) PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease. Neurobiol Dis 45:322-328
75. Chiang MC, Chen CM, Lee MR, Chen HW, Chen HM, Wu YS, Hung CH, Kang JJ, Chang CP, Chang C, Wu YR, Tsai YS, Chern Y (2010) Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferatoractivated receptor gamma. Hum Mol Genet 19:4043-4058
76. Canto C, Auwerx J (2009)PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20:98-105
77. Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, Seredenina T, Arbez N, Zhu S, Sommers K, Qian J, Zhang J, Mori S, Yang XW, Tamashiro KL, Aja S, Moran TH, Luthi-Carter R, Martin B, Maudsley S, Mattson MP, Cichewicz RH, Ross CA, Holtzman DM, Krainc D, Duan W (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med 18:153-158
78. Long YC, Zierath JR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116:1776-1783
79. Ramamurthy S, Ronnett GV (2006) Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. J Physiol 574:85-93
80. Hardie DG (2008) AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes (Lond) 32(Suppl 4):S7-S12
81. Lage R, Dieguez C, Vidal-Puig A, Lopez M (2008) AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 14:539-549
82. Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282:30107-30119
83. Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11:213-219
84. Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251-262
85. Steinberg GR, Kemp BE (2009)AMPK in health and disease. Physiol Rev 89:1025-1078
86. Kemp BE, Mitchelhill KI, Stapleton D, Michell BJ, Chen ZP, Witters LA (1999) Dealing with energy demand: the AMPactivated protein kinase. Trends Biochem Sci 24:22-25
87. Salt I, Celler JW, Hawley SA, Prescott A, Woods A, Carling D, Hardie DG (1998) AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J 334(Pt 1): 177-187
88. Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF (1999) Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem 72:1707-1716
89. Fryer LG, Parbu-Patel A, Carling D (2002) The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226-25232
90. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D (2005)Ca2+/calmodulindependent protein kinase kinase-beta acts upstream of AMPactivated protein kinase in mammalian cells. Cell Metab 2:21-33
91. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005)Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9-19
92. Raney MA, Turcotte LP (2008) Evidence for the involvement of CaMKII and AMPK in Ca2+-dependent signaling pathways regulating FA uptake and oxidation in contracting rodent muscle. J Appl Physiol 104:1366-1373
93. Suzuki A, Kusakai G, Kishimoto A, Shimojo Y, Ogura T, Lavin MF, Esumi H (2004)IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner. Biochem Biophys Res Commun 324:986-992
94. Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M, Mann DL, Taffet GE, Baldini A, Khoury DS, Schneider MD (2006) A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci USA 103:17378-17383
95. Hurley RL, Barre LK, Wood SD, Anderson KA, Kemp BE, Means AR, Witters LA (2006) Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J Biol Chem 281:36662-36672
96. Djouder N, Tuerk RD, Suter M, Salvioni P, Thali RF, Scholz R, Vaahtomeri K, Auchli Y, Rechsteiner H, Brunisholz RA, Viollet B, Makela TP, Wallimann T, Neumann D, Krek W (2010) PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis. EMBO J 29:469-481
97. Lim CT, Kola B, Korbonits M (2010) AMPK as a mediator of hormonal signalling. J Mol Endocrinol 44:87-97
98. Hong YH, Varanasi US, Yang W, Leff T (2003) AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J Biol Chem 278:27495-27501
99. Tsuboi T, da Silva Xavier G, Leclerc I, Rutter GA (2003) 50-AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J Biol Chem 278:52042-52051
100. Cai Y, Martens GA, Hinke SA, Heimberg H, Pipeleers D, Van de Casteele M (2007) Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation. Free Radic Biol Med 42:64-78
101. Kefas BA, Cai Y, Kerckhofs K, Ling Z, Martens G, Heimberg H, Pipeleers D, Van de Casteele M (2004)Metformin-induced stimulation of AMP-activated protein kinase in beta-cells impairs their glucose responsiveness and can lead to apoptosis. Biochem Pharmacol 68:409-416
102. Wang W, Yang X, Kawai T, Lopez de Silanes I,Mazan-Mamczarz K, Chen P, Chook YM, Quensel C, Kohler M, Gorospe M (2004)AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR. J Biol Chem 279:48376-48388
103. Amato S, Liu X, Zheng B, Cantley L, Rakic P, Man HY (2011) AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization. Science 332:247-251
104. Cai Y, Wang Q, Ling Z, Pipeleers D, McDermott P, Pende M, Heimberg H, Van de Casteele M (2008) Akt activation protects pancreatic beta cells from AMPK-mediated death through stimulation of mTOR. Biochem Pharmacol 75:1981-1993
105. Okoshi R, Ozaki T, Yamamoto H, Ando K, Koida N, Ono S, Koda T, Kamijo T, Nakagawara A, Kizaki H (2008) Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J Biol Chem 283:3979-3987
106. Li J, Jiang P, Robinson M, Lawrence TS, Sun Y (2003) AMPKbeta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression. Carcinogenesis 24:827-834
107. Borger DR, Gavrilescu LC, Bucur MC, Ivan M, Decaprio JA (2008) AMP-activated protein kinase is essential for survival in chronic hypoxia. Biochem Biophys Res Commun 370:230-234
108. Culmsee C, Monnig J, Kemp BE, Mattson MP (2001) AMPactivated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17:45-58
109. Terunuma M, Vargas KJ, Wilkins ME, Ramirez OA, Jaureguiberry-Bravo M, Pangalos MN, Smart TG, Moss SJ, Couve A (2010) Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors. Proc Natl Acad Sci USA 107:13918-13923
110. Kuramoto N, Wilkins ME, Fairfax BP, Revilla-Sanchez R, Terunuma M, Tamaki K, Iemata M, Warren N, Couve A, Calver A, Horvath Z, Freeman K, Carling D, Huang L, Gonzales C, Cooper E, Smart TG, Pangalos MN, Moss SJ (2007) Phosphodependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase. Neuron 53:233-247
111. Choi JS, Park C, Jeong JW (2010) AMP-activated protein kinase is activated in Parkinson's disease models mediated by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine. Biochem Biophys Res Commun 391:147-151
112. McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV (2005)Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J Biol Chem 280:20493-20502
113. Lopez-Lopez C, Dietrich MO, Metzger F, Loetscher H, Torres-Aleman I (2007) Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. J Neurosci 27:824-831
114. Shin E, Shin S, Kong H, Lee S, Do SG, Jo TH, Park YI, Lee CK, Hwang IK, Kim K (2011) Dietary aloe reduces adipogenesis via the activation of AMPK and suppresses obesity-related inflammation in obese mice. Immune Netw 11:107-113
115. Thornton C, Bright NJ, Sastre M, Muckett PJ, Carling D (2011) AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J 434:503-512
116. Vingtdeux V, Davies P, Dickson DW, Marambaud P (2011) AMPK is abnormally activated in tangle-and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. Acta Neuropathol 121:337-349
117. Salminen A, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M (2011) AMP-activated protein kinase: a potential player in Alzheimer's disease. J Neurochem 118:460-474
118. Lim MA, Selak MA, Xiang Z, Krainc D, Neve RL, Kraemer BC, Watts JL, Kalb RG (2012) Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease. J Neurosci 32:1123-1141
119. Li J, Benashski S, McCullough LD (2011) Post-stroke hypothermia provides neuroprotection through inhibition of AMPactivated protein kinase. J Neurotrauma 28:1281-1288
120. Li J, Benashski SE, Siegel C, Liu F, McCullough LD (2010) Adenosine monophosphate activated protein kinase inhibition is protective in both sexes after experimental stroke. Neurosci Lett 482:62-65
121. Li J, Zeng Z, Viollet B, Ronnett GV, McCullough LD (2007) Neuroprotective effects of adenosine monophosphate-activated protein kinase inhibition and gene deletion in stroke. Stroke 38:2992-2999
122. Li J, Benashski SE, Venna VR, McCullough LD (2010) Effects of metformin in experimental stroke. Stroke 41:2645-2652
123. Son SM, Jung ES, Shin HJ, Byun J, Mook-Jung I (2012) Abetainduced formation of autophagosomes is mediated by RAGE-CaMKKbeta-AMPK signaling. Neurobiol Aging 33(1006):e1011-e1023
124. Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF (2009)Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA 106:3907-3912
125. Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (2009)Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun 380:98-104
126. Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon JE, Janle EM, Lobo J, Ferruzzi MG, Davies P, Marambaud P (2010) AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem 285:9100-9113
127. Vingtdeux V, Chandakkar P, Zhao H, d'Abramo C, Davies P, Marambaud P (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J 25:219-231
128. Won JS, Im YB, Kim J, Singh AK, Singh I (2010) Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem Biophys Res Commun 399:487-491
129. Chou S-Y, Lee Y-C, Chen H-M, Chiang M-C, Lai H-L, Chang H-H, Wu Y-C, Sun C-N, Chien C-L, Lin Y-S, Wang S-C, Tung Y-Y, Chang C, Chern Y (2005)CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. J Neurochem 93:310-320
130. She P, Zhang Z, Marchionini D, DiazWC, Jetton TJ, Kimball SR, VaryTC, LangCH, LynchCJ (2011)Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. Am J Physiol Endocrinol Metab 301:E49-E61
131. Chaturvedi RK, Calingasan NY, Yang L, Hennessey T, Johri A, Beal MF (2010) Impairment of PGC-1alpha expression, neuropathology and hepatic steatosis in a transgenic mouse model of Huntington's disease following chronic energy deprivation. Hum Mol Genet 19:3190-3205
132. Ma TC, Buescher JL, Oatis B, Funk JA, Nash AJ, Carrier RL, Hoyt KR (2007) Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci Lett 411:98-103
133. Wallimann T (1994) Bioenergetics. Dissecting the role of creatine kinase. Curr Biol 4:42-46
134. Wallimann T, Walzthony D, Wegmann G, Moser H, Eppenberger HM, Barrantes FJ (1985) Subcellular localization of creatine kinase in Torpedo electrocytes: association with acetylcholine receptor-rich membranes. J Cell Biol 100:1063-1072
135. Wyss M, Kaddurah-Daouk R (2000)Creatine and creatinine metabolism. Physiol Rev 80:1107-1213
136. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis. Biochem J 281(Pt 1):21-40
137. Linton JD, Holzhausen LC, Babai N, Song H, Miyagishima KJ, Stearns GW, Lindsay K, Wei J, Chertov AO, Peters TA, Caffe R, Pluk H, Seeliger MW, Tanimoto N, Fong K, Bolton L, Kuok DL, Sweet IR, Bartoletti TM, Radu RA, Travis GH, Zagotta WN, Townes-Anderson E, Parker E, Van der Zee CE, Sampath AP, Sokolov M, Thoreson WB, Hurley JB (2010) Flow of energy in the outer retina in darkness and in light. Proc Natl Acad Sci USA 107:8599-8604
138. Shin JB, Streijger F, Beynon A, Peters T, Gadzala L, McMillen D, Bystrom C, Van der Zee CE, Wallimann T, Gillespie PG (2007) Hair bundles are specialized for ATP delivery via creatine kinase. Neuron 53:371-386
139. Wallimann T, Hemmer W (1994) Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem 133-134:193-220
140. Mahajan VB, Pai KS, Lau A, Cunningham DD (2000)Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton. Proc Natl Acad Sci USA 97:12062-12067
141. Suidan HS, Nobes CD, Hall A, Monard D (1997) Astrocyte spreading in response to thrombin and lysophosphatidic acid is dependent on the Rho GTPase. Glia 21:244-252
142. Gurwitz D, Cunningham DD (1988) Thrombin modulates and reverses neuroblastoma neurite outgrowth. Proc Natl Acad Sci USA 85:3440-3444
143. Suidan HS, Stone SR, Hemmings BA, Monard D (1992) Thrombin causes neurite retraction in neuronal cells through activation of cell surface receptors. Neuron 8:363-375
144. Vaughan PJ, Pike CJ, Cotman CW, Cunningham DD (1995) Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults. J Neurosci 15:5389-5401
145. Inoue K, Ueno S, Fukuda A (2004)Interaction of neuron-specific K?-Cl-cotransporter, KCC2, with brain-type creatine kinase. FEBS Lett 564:131-135
146. Salin-Cantegrel A, Shekarabi M, Holbert S, Dion P, Rochefort D, Laganiere J, Dacal S, Hince P, Karemera L, Gaspar C, Lapointe JY, Rouleau GA (2008) HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K ?/Cl-cotransporter 3. Hum Mol Genet 17:2703-2711
147. Gulacsi A, Lee CR, Sik A, Viitanen T, Kaila K, Tepper JM, Freund TF (2003) Cell type-specific differences in chlorideregulatory mechanisms and GABA(A) receptor-mediated inhibition in rat substantia nigra. J Neurosci 23:8237-8246
148. Race JE, Makhlouf FN, Logue PJ, Wilson FH, Dunham PB, Holtzman EJ (1999) Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Am J Physiol 277:C1210-C1219
149. Howard HC, Mount DB, Rochefort D, Byun N, Dupre N, Lu J, Fan X, Song L, Riviere JB, Prevost C, Horst J, Simonati A, Lemcke B, Welch R, England R, Zhan FQ, Mercado A, Siesser WB, George AL Jr, McDonald MP, Bouchard JP, Mathieu J, Delpire E, Rouleau GA (2002) The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 32:384-392
150. Dupre N, Howard HC, Mathieu J, Karpati G, Vanasse M, Bouchard JP, Carpenter S, Rouleau GA (2003) Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann Neurol 54:9-18
151. Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D (1998) Functional significance of cell volume regulatory mechanisms. Physiol Rev 78:247-306
152. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (1999) The K?/Cl-cotransporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251-255
153. Aksenov MY, Aksenova MV, Payne RM, Smith CD, Markesbery WR, Carney JM (1997) The expression of creatine kinase isoenzymes in neocortex of patients with neurodegenerative disorders: Alzheimer's and Pick's disease. Exp Neurol 146:458-465
154. Aksenova MV, Aksenov MY, Payne RM, Trojanowski JQ, Schmidt ML, Carney JM, Butterfield DA, Markesbery WR (1999) Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders. Dement Geriatr Cogn Disord 10:158-165
155. Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002) Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radic Biol Med 33:562-571
156. Aksenov M, Aksenova M, Butterfield DA, Markesbery WR (2000)Oxidative modification of creatine kinase BB in Alzheimer's disease brain. J Neurochem 74:2520-2527
157. Sorolla MA, Reverter-Branchat G, Tamarit J, Ferrer I, Ros J, Cabiscol E (2008) Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free Radic Biol Med 45:667-678
158. Perluigi M, Poon HF, Maragos W, Pierce WM, Klein JB, Calabrese V, Cini C, De Marco C, Butterfield DA (2005)Proteomic analysis of protein expression and oxidative modification in r6/2 transgenic mice: a model of Huntington disease. Mol Cell Proteomics 4:1849-1861
159. Kim J, Amante DJ, Moody JP, Edgerly CK, Bordiuk OL, Smith K, Matson SA, Matson WR, Scherzer CR, Rosas HD, Hersch SM, Ferrante RJ (2010) Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease. Biochim Biophys Acta 1802:673-681
160. Deschepper M, Hoogendoorn B, Brooks S, Dunnett SB, Jones L (2011) Proteomic changes in the brains of Huntington's disease mouse models reflect pathology and implicate mitochondrial changes. Brain Res Bull http://dx.doi.org/10.1016/j.brainresbull. 2011.01.012
161. Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W, Peters NL, Woods AM, Chan EY, Kooperberg C, Krainc D, Young AB, Tapscott SJ, Olson JM (2002) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 11:1911-1926
162. Zhang SF, Hennessey T, Yang L, Starkova NN, Beal MF, Starkov AA (2011) Impaired brain creatine kinase activity in Huntington's disease. Neurodegener Dis 8:194-201
163. Mochel F, Durant B, Meng X, O'Callaghan J, Yu H, Brouillet E, Wheeler VC, Humbert S, Schiffmann R, Durr A (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 287:1361-1370
164. Li H, Khirug S, Cai C, Ludwig A, Blaesse P, Kolikova J, Afzalov R, Coleman SK, Lauri S, Airaksinen MS, Keinanen K, Khiroug L, Saarma M, Kaila K, Rivera C (2007) KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56:1019-1033
165. Spires TL, Grote HE, Garry S, Cordery PM, Van Dellen A, Blakemore C, Hannan AJ (2004)Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice. Eur J Neurosci 19:2799-2807
166. Choi H, Park CS, Kim BG, Cho JW, Park JB, Bae YS, Bae DS (2001) Creatine kinase B is a target molecule of reactive oxygen species in cervical cancer. Mol Cells 12:412-417
167. Mekhfi H, Veksler V, Mateo P, Maupoil V, Rochette L, Ventura-Clapier R (1996)Creatine kinase is the main target of reactive oxygen species in cardiac myofibrils. Circ Res 78:1016-1027
168. Firdaus WJ, Wyttenbach A, Giuliano P, Kretz-Remy C, Currie RW, Arrigo AP (2006) Huntingtin inclusion bodies are irondependent centers of oxidative events. FEBS J 273:5428-5441
169. Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47-52
170. Klopstock T, Elstner M, Bender A (2011) Creatine in mouse models of neurodegeneration and aging. Amino Acids 40:1297-1303
171. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF (2000)Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci 20:4389-4397
172. Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G, Kaddurah-Daouk R, Beal MF (1999) Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 157:142-149
173. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5:347-350
174. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76:329-343
175. Perasso L, Cupello A, Lunardi GL, Principato C, Gandolfo C, Balestrino M (2003) Kinetics of creatine in blood and brain after intraperitoneal injection in the rat. Brain Res 974:37-42
176. Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward SD, Moran TH, Montell C, Ross CA, Snyder SH, Sawa A (2005)p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 47:29-41
177. Zhao J, Schmieg FI, Simmons DT, Molloy GR (1994) Mouse p53 represses the rat brain creatine kinase gene but activates the rat muscle creatine kinase gene. Mol Cell Biol 14:8483-8492
178. Zhao TJ, Yan YB, Liu Y, Zhou HM (2007) The generation of the oxidized form of creatine kinase is a negative regulation on muscle creatine kinase. J Biol Chem 282:12022-12029
179. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J Neurosci 18:156-163
180. Inoue K, Yamada J, Ueno S, Fukuda A (2006) Brain-type creatine kinase activates neuron-specific K?-Cl-co-transporter KCC2. J Neurochem 96:598-608
181. Stockler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K (1996)Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 58:914-922
182. Item CB, Stockler-Ipsiroglu S, Stromberger C, Muhl A, Alessandri MG, Bianchi MC, Tosetti M, Fornai F, Cioni G (2001) Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69:1127-1133
183. Battini R, Leuzzi V, Carducci C, Tosetti M, Bianchi MC, Item CB, Stockler-Ipsiroglu S, Cioni G (2002) Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 77:326-331
184. Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C (2001) X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68:1497-1500
185. Bizzi A, Bugiani M, Salomons GS, Hunneman DH, Moroni I, Estienne M, Danesi U, Jakobs C, Uziel G (2002) X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. Ann Neurol 52:227-231
186. Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88:1337-1342
187. Zesiewicz TA, Baker MJ, Dunne PB, Hauser RA (2001) Diffuse Lewy Body Disease. Curr Treat Options Neurol 3:507-518
188. Gaig C, Valldeoriola F, Gelpi E, Ezquerra M, Llufriu S, Buongiorno M, Rey MJ, Marti MJ, Graus F, Tolosa E (2011) Rapidly progressive diffuse Lewy body disease. Mov Disord 26:1316-1323
189. Walker FO (2007) Huntington's disease. Semin Neurol 27:143-150
190. Zhang SF, Hennessey T, Yang L, Starkova NN, Beal MF, Starkov AA (2010) Impaired brain creatine kinase activity in Huntington's disease. Neurodegener Dis 8:194-201
191. Boettger T, Rust MB, Maier H, Seidenbecher T, Schweizer M, Keating DJ, Faulhaber J, Ehmke H, Pfeffer C, Scheel O, Lemcke B, Horst J, Leuwer R, Pape HC, Volkl H, Hubner CA, Jentsch TJ (2003) Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J 22:5422-5434