The Biology of Huntingtin

Neuron

Volumn 89, Issue 5, 2016, Pages 910-926

  Saudou, Frédéric ^a,b,c   Humbert, Sandrine ^a,b  

^a UNIV GRENOBLE ALPES   (France)

^b INSERM   (France)

^c GRENOBLE UNIVERSITY HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

HUNTINGTIN; HTT PROTEIN, HUMAN; NERVE PROTEIN;

AUTOPHAGY; CELL DIVISION; CELL MIGRATION; CELL STRUCTURE; CELL SURVIVAL; EMBRYO DEVELOPMENT; ENDOCYTOSIS; GAIN OF FUNCTION MUTATION; HUMAN; HUNTINGTON CHOREA; LOSS OF FUNCTION MUTATION; MOLECULAR BIOLOGY; MUTATIONAL ANALYSIS; NERVE CELL NECROSIS; NEUROBIOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN PROCESSING; REVIEW; TRANSCRIPTION REGULATION; ANIMAL; BIOLOGY; COMPLICATION; GENETICS; METABOLISM; MUTATION; PATHOLOGY;

ANIMALS; BIOLOGY; HUMANS; HUNTINGTON DISEASE; MUTATION; NERVE TISSUE PROTEINS;

EID: 84960441124     PISSN: 08966273     EISSN: 10974199     Source Type: Journal    
DOI: 10.1016/j.neuron.2016.02.003     Document Type: Review

References (151)

1. Aiken C.T., Steffan J.S., Guerrero C.M., Khashwji H., Lukacsovich T., Simmons D., Purcell J.M., Menhaji K., Zhu Y.Z., Green K., et al. Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J. Biol. Chem. 2009, 284:29427-29436.
2. Anne S.L., Saudou F., Humbert S. Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J. Neurosci. 2007, 27:7318-7328.
3. Atwal R.S., Xia J., Pinchev D., Taylor J., Epand R.M., Truant R. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum. Mol. Genet. 2007, 16:2600-2615.
4. Aylward E.H., Nopoulos P.C., Ross C.A., Langbehn D.R., Pierson R.K., Mills J.A., Johnson H.J., Magnotta V.A., Juhl A.R., Paulsen J.S. Longitudinal change in regional brain volumes in prodromal Huntington disease. J. Neurol. Neurosurg. Psychiatry 2011, 82:405-410. PREDICT-HD Investigators and Coordinators of Huntington Study Group.
5. Badano J.L., Teslovich T.M., Katsanis N. The centrosome in human genetic disease. Nat. Rev. Genet. 2005, 6:194-205.
6. Bae B.I., Xu H., Igarashi S., Fujimuro M., Agrawal N., Taya Y., Hayward S.D., Moran T.H., Montell C., Ross C.A., et al. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 2005, 47:29-41.
7. Baquet Z.C., Gorski J.A., Jones K.R. Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J. Neurosci. 2004, 24:4250-4258.
8. Bečanović K., Nørremølle A., Neal S.J., Kay C., Collins J.A., Arenillas D., Lilja T., Gaudenzi G., Manoharan S., Doty C.N., et al. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nat. Neurosci. 2015, 18:807-816. REGISTRY Investigators of the European Huntington's Disease Network.
9. Ben M'Barek K., Pla P., Orvoen S., Benstaali C., Godin J.D., Gardier A.M., Saudou F., David D.J., Humbert S. Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis. J. Neurosci. 2013, 33:8608-8620.
10. Benn C.L., Landles C., Li H., Strand A.D., Woodman B., Sathasivam K., Li S.H., Ghazi-Noori S., Hockly E., Faruque S.M., et al. Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease. Hum. Mol. Genet. 2005, 14:3065-3078.
11. Benn C.L., Sun T., Sadri-Vakili G., McFarland K.N., DiRocco D.P., Yohrling G.J., Clark T.W., Bouzou B., Cha J.H. Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J. Neurosci. 2008, 28:10720-10733.
12. Borrell-Pagès M., Zala D., Humbert S., Saudou F. Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell. Mol. Life Sci. 2006, 63:2642-2660.
13. Caviston J.P., Ross J.L., Antony S.M., Tokito M., Holzbaur E.L. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl. Acad. Sci. USA 2007, 104:10045-10050.
14. Caviston J.P., Zajac A.L., Tokito M., Holzbaur E.L. Huntingtin coordinates the dynein-mediated dynamic positioning of endosomes and lysosomes. Mol. Biol. Cell 2011, 22:478-492.
15. Colin E., Zala D., Liot G., Rangone H., Borrell-Pagès M., Li X.J., Saudou F., Humbert S. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 2008, 27:2124-2134.
16. Cong X., Held J.M., DeGiacomo F., Bonner A., Chen J.M., Schilling B., Czerwieniec G.A., Gibson B.W., Ellerby L.M. Mass spectrometric identification of novel lysine acetylation sites in huntingtin. Mol. Cell Proteomics 2011, 10. M111.009829.
17. Costa V., Giacomello M., Hudec R., Lopreiato R., Ermak G., Lim D., Malorni W., Davies K.J., Carafoli E., Scorrano L. Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli. EMBO Mol. Med. 2010, 2:490-503.
18. Culver B.P., Savas J.N., Park S.K., Choi J.H., Zheng S., Zeitlin S.O., Yates J.R., Tanese N. Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis. J. Biol. Chem. 2012, 287:21599-21614.
19. Davies S.W., Turmaine M., Cozens B.A., DiFiglia M., Sharp A.H., Ross C.A., Scherzinger E., Wanker E.E., Mangiarini L., Bates G.P. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997, 90:537-548.
20. del Toro D., Alberch J., Lázaro-Diéguez F., Martín-Ibáñez R., Xifró X., Egea G., Canals J.M. Mutant huntingtin impairs post-Golgi trafficking to lysosomes by delocalizing optineurin/Rab8 complex from the Golgi apparatus. Mol. Biol. Cell 2009, 20:1478-1492.
21. Dietrich P., Shanmugasundaram R., Shuyu E., Dragatsis I. Congenital hydrocephalus associated with abnormal subcommissural organ in mice lacking huntingtin in Wnt1 cell lineages. Hum. Mol. Genet. 2009, 18:142-150.
22. Dong G., Callegari E., Gloeckner C.J., Ueffing M., Wang H. Mass spectrometric identification of novel posttranslational modification sites in Huntingtin. Proteomics 2012, 12:2060-2064.
23. Dragatsis I., Efstratiadis A., Zeitlin S. Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues. Development 1998, 125:1529-1539.
24. Dragatsis I., Levine M.S., Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 2000, 26:300-306.
25. Drouet V., Ruiz M., Zala D., Feyeux M., Auregan G., Cambon K., Troquier L., Carpentier J., Aubert S., Merienne N., et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS ONE 2014, 9:e99341.
26. Dunah A.W., Jeong H., Griffin A., Kim Y.M., Standaert D.G., Hersch S.M., Mouradian M.M., Young A.B., Tanese N., Krainc D. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 2002, 296:2238-2243.
27. Duyao M.P., Auerbach A.B., Ryan A., Persichetti F., Barnes G.T., McNeil S.M., Ge P., Vonsattel J.P., Gusella J.F., Joyner A.L., et al. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 1995, 269:407-410.
28. El-Daher M.T., Hangen E., Bruyère J., Poizat G., Al-Ramahi I., Pardo R., Bourg N., Souquere S., Mayet C., Pierron G., et al. Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 2015, 34:2255-2271.
29. Elias S., Thion M.S., Yu H., Sousa C.M., Lasgi C., Morin X., Humbert S. Huntingtin regulates mammary stem cell division and differentiation. Stem Cell Reports 2014, 2:491-506.
30. Elias S., McGuire J.R., Yu H., Humbert S. Huntingtin Is Required for Epithelial Polarity through RAB11A-Mediated Apical Trafficking of PAR3-aPKC. PLoS Biol. 2015, 13:e1002142.
31. Engelender S., Sharp A.H., Colomer V., Tokito M.K., Lanahan A., Worley P., Holzbaur E.L., Ross C.A. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum. Mol. Genet. 1997, 6:2205-2212.
32. Engqvist-Goldstein A.E., Warren R.A., Kessels M.M., Keen J.H., Heuser J., Drubin D.G. The actin-binding protein Hip1R associates with clathrin during early stages of endocytosis and promotes clathrin assembly in vitro. J. Cell Biol. 2001, 154:1209-1223.
33. Faber P.W., Barnes G.T., Srinidhi J., Chen J., Gusella J.F., MacDonald M.E. Huntingtin interacts with a family of WW domain proteins. Hum. Mol. Genet. 1998, 7:1463-1474.
34. Futter M., Diekmann H., Schoenmakers E., Sadiq O., Chatterjee K., Rubinsztein D.C. Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors. J. Med. Genet. 2009, 46:438-446.
35. Gafni J., Ellerby L.M. Calpain activation in Huntington's disease. J. Neurosci. 2002, 22:4842-4849.
36. Gauthier L.R., Charrin B.C., Borrell-Pagès M., Dompierre J.P., Rangone H., Cordelières F.P., De Mey J., MacDonald M.E., Lessmann V., Humbert S., Saudou F. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004, 118:127-138.
37. Godin J.D., Colombo K., Molina-Calavita M., Keryer G., Zala D., Charrin B.C., Dietrich P., Volvert M.L., Guillemot F., Dragatsis I., et al. Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron 2010, 67:392-406.
38. Goehler H., Lalowski M., Stelzl U., Waelter S., Stroedicke M., Worm U., Droege A., Lindenberg K.S., Knoblich M., Haenig C., et al. A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Mol. Cell 2004, 15:853-865.
39. Goldberg Y.P., Nicholson D.W., Rasper D.M., Kalchman M.A., Koide H.B., Graham R.K., Bromm M., Kazemi-Esfarjani P., Thornberry N.A., Vaillancourt J.P., Hayden M.R. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat. Genet. 1996, 13:442-449.
40. Graham R.K., Deng Y., Slow E.J., Haigh B., Bissada N., Lu G., Pearson J., Shehadeh J., Bertram L., Murphy Z., et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 2006, 125:1179-1191.
41. Gray M., Shirasaki D.I., Cepeda C., André V.M., Wilburn B., Lu X.H., Tao J., Yamazaki I., Li S.H., Sun Y.E., et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci. 2008, 28:6182-6195.
42. Gunawardena S., Her L.S., Brusch R.G., Laymon R.A., Niesman I.R., Gordesky-Gold B., Sintasath L., Bonini N.M., Goldstein L.S. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 2003, 40:25-40.
43. Gutekunst C.A., Levey A.I., Heilman C.J., Whaley W.L., Yi H., Nash N.R., Rees H.D., Madden J.J., Hersch S.M. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc. Natl. Acad. Sci. USA 1995, 92:8710-8714.
44. Haremaki T., Deglincerti A., Brivanlou A.H. Huntingtin is required for ciliogenesis and neurogenesis during early Xenopus development. Dev. Biol. 2015, 408:305-315.
45. Harjes P., Wanker E.E. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem. Sci. 2003, 28:425-433.
46. Hattula K., Peränen J. FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis. Curr. Biol. 2000, 10:1603-1606.
47. Her L.S., Goldstein L.S. Enhanced sensitivity of striatal neurons to axonal transport defects induced by mutant huntingtin. J. Neurosci. 2008, 28:13662-13672.
48. Hermel E., Gafni J., Propp S.S., Leavitt B.R., Wellington C.L., Young J.E., Hackam A.S., Logvinova A.V., Peel A.L., Chen S.F., et al. Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death Differ. 2004, 11:424-438.
49. Ho L.W., Brown R., Maxwell M., Wyttenbach A., Rubinsztein D.C. Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease. J. Med. Genet. 2001, 38:450-452.
50. Holbert S., Denghien I., Kiechle T., Rosenblatt A., Wellington C., Hayden M.R., Margolis R.L., Ross C.A., Dausset J., Ferrante R.J., Néri C. The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis. Proc. Natl. Acad. Sci. USA 2001, 98:1811-1816.
51. Huang K., Sanders S.S., Kang R., Carroll J.B., Sutton L., Wan J., Singaraja R., Young F.B., Liu L., El-Husseini A., et al. Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14. Hum. Mol. Genet. 2011, 20:3356-3365.
52. Huang B., Lucas T., Kueppers C., Dong X., Krause M., Bepperling A., Buchner J., Voshol H., Weiss A., Gerrits B., Kochanek S. Scalable production in human cells and biochemical characterization of full-length normal and mutant huntingtin. PLoS ONE 2015, 10:e0121055.
53. Hughes A.C., Mort M., Elliston L., Thomas R.M., Brooks S.P., Dunnett S.B., Jones L. Identification of novel alternative splicing events in the huntingtin gene and assessment of the functional consequences using structural protein homology modelling. J. Mol. Biol. 2014, 426:1428-1438.
54. Humbert S., Bryson E.A., Cordelières F.P., Connors N.C., Datta S.R., Finkbeiner S., Greenberg M.E., Saudou F. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev. Cell 2002, 2:831-837.
55. Jeong H., Then F., Melia T.J., Mazzulli J.R., Cui L., Savas J.N., Voisine C., Paganetti P., Tanese N., Hart A.C., et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009, 137:60-72.
56. Kaltenbach L.S., Romero E., Becklin R.R., Chettier R., Bell R., Phansalkar A., Strand A., Torcassi C., Savage J., Hurlburt A., et al. Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet. 2007, 3:e82.
57. Karam A., Tebbe L., Weber C., Messaddeq N., Morlé L., Kessler P., Wolfrum U., Trottier Y. A novel function of Huntingtin in the cilium and retinal ciliopathy in Huntington's disease mice. Neurobiol. Dis. 2015, 80:15-28.
58. Kegel K.B., Kim M., Sapp E., McIntyre C., Castaño J.G., Aronin N., DiFiglia M. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J. Neurosci. 2000, 20:7268-7278.
59. Kegel K.B., Meloni A.R., Yi Y., Kim Y.J., Doyle E., Cuiffo B.G., Sapp E., Wang Y., Qin Z.H., Chen J.D., et al. Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J. Biol. Chem. 2002, 277:7466-7476.
60. Keryer G., Pineda J.R., Liot G., Kim J., Dietrich P., Benstaali C., Smith K., Cordelières F.P., Spassky N., Ferrante R.J., et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 2011, 121:4372-4382.
61. Kim Y.J., Yi Y., Sapp E., Wang Y., Cuiffo B., Kegel K.B., Qin Z.H., Aronin N., DiFiglia M. Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc. Natl. Acad. Sci. USA 2001, 98:12784-12789.
62. Kim Y.J., Sapp E., Cuiffo B.G., Sobin L., Yoder J., Kegel K.B., Qin Z.H., Detloff P., Aronin N., DiFiglia M. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol. Dis. 2006, 22:346-356.
63. Kim M.W., Chelliah Y., Kim S.W., Otwinowski Z., Bezprozvanny I. Secondary structure of Huntingtin amino-terminal region. Structure 2009, 17:1205-1212.
64. Kremer B., Goldberg P., Andrew S.E., Theilmann J., Telenius H., Zeisler J., Squitieri F., Lin B., Bassett A., Almqvist E., et al. A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N. Engl. J. Med. 1994, 330:1401-1406.
65. Leavitt B.R., van Raamsdonk J.M., Shehadeh J., Fernandes H., Murphy Z., Graham R.K., Wellington C.L., Raymond L.A., Hayden M.R. Wild-type huntingtin protects neurons from excitotoxicity. J. Neurochem. 2006, 96:1121-1129.
66. Lee J.M., Ramos E.M., Lee J.H., Gillis T., Mysore J.S., Hayden M.R., Warby S.C., Morrison P., Nance M., Ross C.A., et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 2012, 78:690-695. PREDICT-HD study of the Huntington Study Group (HSG), REGISTRY study of the European Huntington's Disease NetworkREGISTRY study of the European Huntington's Disease Network, HD-MAPS Study GroupHD-MAPS Study Group, COHORT study of the HSGCOHORT study of the HSG.
67. Legendre-Guillemin V., Metzler M., Charbonneau M., Gan L., Chopra V., Philie J., Hayden M.R., McPherson P.S. HIP1 and HIP12 display differential binding to F-actin, AP2, and clathrin. Identification of a novel interaction with clathrin light chain. J. Biol. Chem. 2002, 277:19897-19904.
68. Li S.H., Gutekunst C.A., Hersch S.M., Li X.J. Interaction of huntingtin-associated protein with dynactin P150Glued. J. Neurosci. 1998, 18:1261-1269.
69. Li S.H., Cheng A.L., Zhou H., Lam S., Rao M., Li H., Li X.J. Interaction of Huntington disease protein with transcriptional activator Sp1. Mol. Cell. Biol. 2002, 22:1277-1287.
70. Li W., Serpell L.C., Carter W.J., Rubinsztein D.C., Huntington J.A. Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein. J. Biol. Chem. 2006, 281:15916-15922.
71. Li X., Sapp E., Valencia A., Kegel K.B., Qin Z.H., Alexander J., Masso N., Reeves P., Ritch J.J., Zeitlin S., et al. A function of huntingtin in guanine nucleotide exchange on Rab11. Neuroreport 2008, 19:1643-1647.
72. Lin B., Rommens J.M., Graham R.K., Kalchman M., MacDonald H., Nasir J., Delaney A., Goldberg Y.P., Hayden M.R. Differential 3' polyadenylation of the Huntington disease gene results in two mRNA species with variable tissue expression. Hum. Mol. Genet. 1993, 2:1541-1545.
73. Liot G., Zala D., Pla P., Mottet G., Piel M., Saudou F. Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J. Neurosci. 2013, 33:6298-6309.
74. Lo Sardo V., Zuccato C., Gaudenzi G., Vitali B., Ramos C., Tartari M., Myre M.A., Walker J.A., Pistocchi A., Conti L., et al. An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin. Nat. Neurosci. 2012, 15:713-721.
75. Lumsden A.L., Henshall T.L., Dayan S., Lardelli M.T., Richards R.I. Huntingtin-deficient zebrafish exhibit defects in iron utilization and development. Hum. Mol. Genet. 2007, 16:1905-1920.
76. Lunkes A., Lindenberg K.S., Ben-Haïem L., Weber C., Devys D., Landwehrmeyer G.B., Mandel J.L., Trottier Y. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell 2002, 10:259-269.
77. Luo S., Vacher C., Davies J.E., Rubinsztein D.C. Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J. Cell Biol. 2005, 169:647-656.
78. Maiuri T., Woloshansky T., Xia J., Truant R. The huntingtin N17 domain is a multifunctional CRM1 and Ran-dependent nuclear and cilial export signal. Hum. Mol. Genet. 2013, 22:1383-1394.
79. Marcora E., Gowan K., Lee J.E. Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2. Proc. Natl. Acad. Sci. USA 2003, 100:9578-9583.
80. Marques Sousa C., Humbert S. Huntingtin: here, there, everywhere!. J. Huntingtons Dis. 2013, 2:395-403.
81. Martin D.D., Heit R.J., Yap M.C., Davidson M.W., Hayden M.R., Berthiaume L.G. Identification of a post-translationally myristoylated autophagy-inducing domain released by caspase cleavage of huntingtin. Hum. Mol. Genet. 2014, 23:3166-3179.
82. Martinez-Vicente M., Talloczy Z., Wong E., Tang G., Koga H., Kaushik S., de Vries R., Arias E., Harris S., Sulzer D., Cuervo A.M. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 2010, 13:567-576.
83. McGuire J.R., Rong J., Li S.H., Li X.J. Interaction of Huntingtin-associated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons. J. Biol. Chem. 2006, 281:3552-3559.
84. Menalled L., El-Khodor B.F., Patry M., Suárez-Fariñas M., Orenstein S.J., Zahasky B., Leahy C., Wheeler V., Yang X.W., MacDonald M., et al. Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiol. Dis. 2009, 35:319-336.
85. Miller J., Arrasate M., Shaby B.A., Mitra S., Masliah E., Finkbeiner S. Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington's disease molecular pathogenesis. J. Neurosci. 2010, 30:10541-10550.
86. Modregger J., Schmidt A.A., Ritter B., Huttner W.B., Plomann M. Characterization of Endophilin B1b, a brain-specific membrane-associated lysophosphatidic acid acyl transferase with properties distinct from endophilin A1. J. Biol. Chem. 2003, 278:4160-4167.
87. Moreira Sousa C., McGuire J.R., Thion M.S., Gentien D., de la Grange P., Tezenas du Montcel S., Vincent-Salomon A., Durr A., Humbert S. The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling. EMBO Mol. Med. 2013, 5:309-325.
88. Moritz A., Li Y., Guo A., Villén J., Wang Y., MacNeill J., Kornhauser J., Sprott K., Zhou J., Possemato A., et al. Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci. Signal. 2010, 3:ra64.
89. Nasir J., Floresco S.B., O'Kusky J.R., Diewert V.M., Richman J.M., Zeisler J., Borowski A., Marth J.D., Phillips A.G., Hayden M.R. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995, 81:811-823.
90. Neveklovska M., Clabough E.B., Steffan J.S., Zeitlin S.O. Deletion of the huntingtin proline-rich region does not significantly affect normal huntingtin function in mice. J. Huntingtons Dis. 2012, 1:71-87.
91. O'Kusky J.R., Nasir J., Cicchetti F., Parent A., Hayden M.R. Neuronal degeneration in the basal ganglia and loss of pallido-subthalamic synapses in mice with targeted disruption of the Huntington's disease gene. Brain Res. 1999, 818:468-479.
92. Ochaba J., Lukacsovich T., Csikos G., Zheng S., Margulis J., Salazar L., Mao K., Lau A.L., Yeung S.Y., Humbert S., et al. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc. Natl. Acad. Sci. USA 2014, 111:16889-16894.
93. Orr H.T. Polyglutamine neurodegeneration: expanded glutamines enhance native functions. Curr. Opin. Genet. Dev. 2012, 22:251-255.
94. Orr A.L., Li S., Wang C.E., Li H., Wang J., Rong J., Xu X., Mastroberardino P.G., Greenamyre J.T., Li X.J. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J. Neurosci. 2008, 28:2783-2792.
95. Pal A., Severin F., Lommer B., Shevchenko A., Zerial M. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease. J. Cell Biol. 2006, 172:605-618.
96. Palidwor G.A., Shcherbinin S., Huska M.R., Rasko T., Stelzl U., Arumughan A., Foulle R., Porras P., Sanchez-Pulido L., Wanker E.E., Andrade-Navarro M.A. Detection of alpha-rod protein repeats using a neural network and application to huntingtin. PLoS Comput. Biol. 2009, 5:e1000304.
97. Pardo R., Colin E., Régulier E., Aebischer P., Déglon N., Humbert S., Saudou F. Inhibition of calcineurin by FK506 protects against polyglutamine-huntingtin toxicity through an increase of huntingtin phosphorylation at S421. J. Neurosci. 2006, 26:1635-1645.
98. Pouladi M.A., Xie Y., Skotte N.H., Ehrnhoefer D.E., Graham R.K., Kim J.E., Bissada N., Yang X.W., Paganetti P., Friedlander R.M., et al. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum. Mol. Genet. 2010, 19:1528-1538.
99. Rangone H., Poizat G., Troncoso J., Ross C.A., MacDonald M.E., Saudou F., Humbert S. The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur. J. Neurosci. 2004, 19:273-279.
100. Ratovitski T., Gucek M., Jiang H., Chighladze E., Waldron E., D'Ambola J., Hou Z., Liang Y., Poirier M.A., Hirschhorn R.R., et al. Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. J. Biol. Chem. 2009, 284:10855-10867.
101. Ratovitski T., Chighladze E., Arbez N., Boronina T., Herbrich S., Cole R.N., Ross C.A. Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis. Cell Cycle 2012, 11:2006-2021.
102. Ravikumar B., Vacher C., Berger Z., Davies J.E., Luo S., Oroz L.G., Scaravilli F., Easton D.F., Duden R., O'Kane C.J., Rubinsztein D.C. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 2004, 36:585-595.
103. Reiner A., Del Mar N., Meade C.A., Yang H., Dragatsis I., Zeitlin S., Goldowitz D. Neurons lacking huntingtin differentially colonize brain and survive in chimeric mice. J. Neurosci. 2001, 21:7608-7619.
104. Rigamonti D., Sipione S., Goffredo D., Zuccato C., Fossale E., Cattaneo E. Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing. J. Biol. Chem. 2001, 276:14545-14548.
105. Rockabrand E., Slepko N., Pantalone A., Nukala V.N., Kazantsev A., Marsh J.L., Sullivan P.G., Steffan J.S., Sensi S.L., Thompson L.M. The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum. Mol. Genet. 2007, 16:61-77.
106. Rosas H.D., Salat D.H., Lee S.Y., Zaleta A.K., Pappu V., Fischl B., Greve D., Hevelone N., Hersch S.M. Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity. Brain 2008, 131:1057-1068.
107. Ross C.A., Tabrizi S.J. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011, 10:83-98.
108. Rui Y.N., Xu Z., Patel B., Chen Z., Chen D., Tito A., David G., Sun Y., Stimming E.F., Bellen H.J., et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 2015, 17:262-275.
109. Ruzo A., Ismailoglu I., Popowski M., Haremaki T., Croft G.F., Deglincerti A., Brivanlou A.H. Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon. PLoS ONE 2015, 10:e0127687.
110. Sahlender D.A., Roberts R.C., Arden S.D., Spudich G., Taylor M.J., Luzio J.P., Kendrick-Jones J., Buss F. Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J. Cell Biol. 2005, 169:285-295.
111. Saudou F., Finkbeiner S., Devys D., Greenberg M.E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998, 95:55-66.
112. Schaefer M.H., Fontaine J.F., Vinayagam A., Porras P., Wanker E.E., Andrade-Navarro M.A. HIPPIE: Integrating protein interaction networks with experiment based quality scores. PLoS ONE 2012, 7:e31826.
113. Schilling B., Gafni J., Torcassi C., Cong X., Row R.H., LaFevre-Bernt M.A., Cusack M.P., Ratovitski T., Hirschhorn R., Ross C.A., et al. Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity. J. Biol. Chem. 2006, 281:23686-23697.
114. Seong I.S., Woda J.M., Song J.J., Lloret A., Abeyrathne P.D., Woo C.J., Gregory G., Lee J.M., Wheeler V.C., Walz T., et al. Huntingtin facilitates polycomb repressive complex 2. Hum. Mol. Genet. 2010, 19:573-583.
115. Shimojo M. Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150 Glued. J. Biol. Chem. 2008, 283:34880-34886.
116. Shirasaki D.I., Greiner E.R., Al-Ramahi I., Gray M., Boontheung P., Geschwind D.H., Botas J., Coppola G., Horvath S., Loo J.A., Yang X.W. Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 2012, 75:41-57.
117. Sittler A., Wälter S., Wedemeyer N., Hasenbank R., Scherzinger E., Eickhoff H., Bates G.P., Lehrach H., Wanker E.E. SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol. Cell 1998, 2:427-436.
118. Song W., Chen J., Petrilli A., Liot G., Klinglmayr E., Zhou Y., Poquiz P., Tjong J., Pouladi M.A., Hayden M.R., et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat. Med. 2011, 17:377-382.
119. Steffan J.S. Does Huntingtin play a role in selective macroautophagy?. Cell Cycle 2010, 9:3401-3413.
120. Steffan J.S., Kazantsev A., Spasic-Boskovic O., Greenwald M., Zhu Y.Z., Gohler H., Wanker E.E., Bates G.P., Housman D.E., Thompson L.M. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA 2000, 97:6763-6768.
121. Steffan J.S., Agrawal N., Pallos J., Rockabrand E., Trotman L.C., Slepko N., Illes K., Lukacsovich T., Zhu Y.Z., Cattaneo E., et al. SUMO modification of Huntingtin and Huntington's disease pathology. Science 2004, 304:100-104.
122. Strehlow A.N., Li J.Z., Myers R.M. Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space. Hum. Mol. Genet. 2007, 16:391-409.
123. Tabrizi S.J., Langbehn D.R., Leavitt B.R., Roos R.A., Durr A., Craufurd D., Kennard C., Hicks S.L., Fox N.C., Scahill R.I., et al. Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009, 8:791-801. TRACK-HD investigators.
124. Takano H., Gusella J.F. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci. 2002, 3:15.
125. Tartari M., Gissi C., Lo Sardo V., Zuccato C., Picardi E., Pesole G., Cattaneo E. Phylogenetic comparison of huntingtin homologues reveals the appearance of a primitive polyQ in sea urchin. Mol. Biol. Evol. 2008, 25:330-338.
126. Tebbenkamp A.T., Crosby K.W., Siemienski Z.B., Brown H.H., Golde T.E., Borchelt D.R. Analysis of proteolytic processes and enzymatic activities in the generation of huntingtin n-terminal fragments in an HEK293 cell model. PLoS ONE 2012, 7:e50750.
127. Thion M.S., McGuire J.R., Sousa C.M., Fuhrmann L., Fitamant J., Leboucher S., Vacher S., du Montcel S.T., Bièche I., Bernet A., et al. Unraveling the Role of Huntingtin in Breast Cancer Metastasis. J. Natl. Cancer Inst. 2015, 107:djv208.
128. Thompson L.M., Aiken C.T., Kaltenbach L.S., Agrawal N., Illes K., Khoshnan A., Martinez-Vincente M., Arrasate M., O'Rourke J.G., Khashwji H., et al. IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J. Cell Biol. 2009, 187:1083-1099.
129. Tong Y., Ha T.J., Liu L., Nishimoto A., Reiner A., Goldowitz D. Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. J. Neurosci. 2011, 31:14794-14799.
130. Trushina E., Dyer R.B., Badger J.D., Ure D., Eide L., Tran D.D., Vrieze B.T., Legendre-Guillemin V., McPherson P.S., Mandavilli B.S., et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell. Biol. 2004, 24:8195-8209.
131. Twelvetrees A.E., Yuen E.Y., Arancibia-Carcamo I.L., MacAskill A.F., Rostaing P., Lumb M.J., Humbert S., Triller A., Saudou F., Yan Z., Kittler J.T. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 2010, 65:53-65.
132. Valor L.M. Transcription, epigenetics and ameliorative strategies in Huntington's Disease: a genome-wide perspective. Mol. Neurobiol. 2015, 51:406-423.
133. van der Burg J.M., Björkqvist M., Brundin P. Beyond the brain: widespread pathology in Huntington's disease. Lancet Neurol. 2009, 8:765-774.
134. Van Raamsdonk J.M., Pearson J., Rogers D.A., Bissada N., Vogl A.W., Hayden M.R., Leavitt B.R. Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 2005, 14:1379-1392.
135. Van Raamsdonk J.M., Gibson W.T., Pearson J., Murphy Z., Lu G., Leavitt B.R., Hayden M.R. Body weight is modulated by levels of full-length huntingtin. Hum. Mol. Genet. 2006, 15:1513-1523.
136. Waelter S., Scherzinger E., Hasenbank R., Nordhoff E., Lurz R., Goehler H., Gauss C., Sathasivam K., Bates G.P., Lehrach H., Wanker E.E. The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis. Hum. Mol. Genet. 2001, 10:1807-1817.
137. Warby S.C., Doty C.N., Graham R.K., Carroll J.B., Yang Y.Z., Singaraja R.R., Overall C.M., Hayden M.R. Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum. Mol. Genet. 2008, 17:2390-2404.
138. Watkin E.E., Arbez N., Waldron-Roby E., O'Meally R., Ratovitski T., Cole R.N., Ross C.A. Phosphorylation of mutant huntingtin at serine 116 modulates neuronal toxicity. PLoS ONE 2014, 9:e88284.
139. White J.K., Auerbach W., Duyao M.P., Vonsattel J.P., Gusella J.F., Joyner A.L., MacDonald M.E. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat. Genet. 1997, 17:404-410.
140. Wong Y.C., Holzbaur E.L. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 2014, 34:1293-1305.
141. Xia J., Lee D.H., Taylor J., Vandelft M., Truant R. Huntingtin contains a highly conserved nuclear export signal. Hum. Mol. Genet. 2003, 12:1393-1403.
142. Yanai A., Huang K., Kang R., Singaraja R.R., Arstikaitis P., Gan L., Orban P.C., Mullard A., Cowan C.M., Raymond L.A., et al. Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat. Neurosci. 2006, 9:824-831.
143. Yohrling G.J., Farrell L.A., Hollenberg A.N., Cha J.H. Mutant huntingtin increases nuclear corepressor function and enhances ligand-dependent nuclear hormone receptor activation. Mol. Cell. Neurosci. 2003, 23:28-38.
144. Zala D., Hinckelmann M.V., Saudou F. Huntingtin's function in axonal transport is conserved in Drosophila melanogaster. PLoS ONE 2013, 8:e60162.
145. Zala D., Hinckelmann M.V., Yu H., Lyra da Cunha M.M., Liot G., Cordelières F.P., Marco S., Saudou F. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 2013, 152:479-491.
146. Zeitlin S., Liu J.P., Chapman D.L., Papaioannou V.E., Efstratiadis A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat. Genet. 1995, 11:155-163.
147. Zhang Y., Li M., Drozda M., Chen M., Ren S., Mejia Sanchez R.O., Leavitt B.R., Cattaneo E., Ferrante R.J., Hayden M.R., Friedlander R.M. Depletion of wild-type huntingtin in mouse models of neurologic diseases. J. Neurochem. 2003, 87:101-106.
148. Zhang Y., Leavitt B.R., van Raamsdonk J.M., Dragatsis I., Goldowitz D., MacDonald M.E., Hayden M.R., Friedlander R.M. Huntingtin inhibits caspase-3 activation. EMBO J. 2006, 25:5896-5906.
149. Zheng S., Clabough E.B., Sarkar S., Futter M., Rubinsztein D.C., Zeitlin S.O. Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet. 2010, 6:e1000838.
150. Zuccato C., Ciammola A., Rigamonti D., Leavitt B.R., Goffredo D., Conti L., MacDonald M.E., Friedlander R.M., Silani V., Hayden M.R., et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 2001, 293:493-498.
151. Zuccato C., Tartari M., Crotti A., Goffredo D., Valenza M., Conti L., Cataudella T., Leavitt B.R., Hayden M.R., Timmusk T., et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat. Genet. 2003, 35:76-83.