Experimental mutagenesis of huntingtin to map cleavage sites: Different outcomes in cell and mouse models

Journal of Huntington's Disease

Volumn 3, Issue 1, 2014, Pages 73-86

  Tebbenkamp, Andrew T N ^a,d   Xu, Guilian ^a,b   Siemienski, Zoe B ^a,b   Janus, Christopher ^a,b   Fromholt, Susan E ^a,b   Brown, Hilda H ^a,b   Swing, Debbie ^c   Tessarollo, Lino ^c   Borchelt, David R ^a,b  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF FLORIDA   (United States)

^c NATIONAL CANCER INSTITUTE   (United States)

^d YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Huntington's disease; intranuclear inclusion bodies; mutagenesis; protease; protein processing; transgenic mice

Indexed keywords

AMINO ACID; HUNTINGTIN; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY 2B4; MONOCLONAL ANTIBODY EM48; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL NUCLEUS INCLUSION BODY; CEREBELLUM; CONTROLLED STUDY; GENE MUTATION; HEK293 CELL LINE; HUMAN; HUMAN CELL; HUNTINGTON CHOREA; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; IN VIVO STUDY; MOTOR COORDINATION; MOUSE; MUTAGENESIS; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; STOP CODON;

HUNTINGTON'S DISEASE; INTRANUCLEAR INCLUSION BODIES; MUTAGENESIS; PROTEASE; PROTEIN PROCESSING; TRANSGENIC MICE;

ANIMALS; BRAIN; DISEASE MODELS, ANIMAL; HEK293 CELLS; HUMANS; HUNTINGTON DISEASE; INCLUSION BODIES; MICE; MICE, TRANSGENIC; MUTAGENESIS; MUTANT PROTEINS; NERVE TISSUE PROTEINS; NUCLEAR PROTEINS; PEPTIDE FRAGMENTS; PHENOTYPE;

EID: 84908093834     PISSN: 18796397     EISSN: 18796400     Source Type: Journal    
DOI: 10.3233/JHD-130087     Document Type: Article

References (29)

1. Vonsattel JP. Huntington disease models and human neuropathology: Similarities and differences. Acta Neuropathologica. 2008;115(1):55-69. (Pubitemid 50000780)
2. Vonsattel JP, Keller C, Cortes Ramirez EP. Huntington's disease - neuropathology. Handb Clin Neurol. 2011;100: 83-100.
3. Sieradzan KA, Mechan AO, Jones L, Wanker EE, Nukina N, Mann DM. Huntington's disease intranuclear inclusions contain truncated: Ubiquitinated huntingtin protein. Exp Neurol 1999;156(1):92-9. (Pubitemid 29152986)
4. Wang CE, Tydlacka S, Orr AL, Yang SH, Graham RK, Hayden MR, Li S, Chan AW, Li XJ. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease. Hum Mol Genet. 2008;17(17):2738-51.
5. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;277:1990-3. (Pubitemid 27449140)
6. Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante RJ, Hersch SM, Li XJ. Nuclear and neuropil aggregates in Huntington's disease: Relationship to neuropathology. J Neurosci. 1999;19:2522-34. (Pubitemid 29162401)
7. Lunkes A, Lindenberg KS, Ben Haiem L,Weber C, Devys D, Landwehrmeyer GB, Mandel JL, Trottier Y. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell. 2002;10(2):259-69. (Pubitemid 35007341)
8. Kim YJ, Sapp E, Cuiffo BG, Sobin L, Yoder J, Kegel KB, Qin ZH, Detloff P, Aronin N, DiFiglia M. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis. 2006;22(2):346-56.
9. Ratovitski T, Nakamura M, D'Ambola J, Chighladze E, Liang Y,WangW, Graham R, HaydenMR,Borchelt DR, Hirschhorn RR, Ross CA. N-terminal proteolysis of full-length mutant huntingtin in an inducible PC12 cell model of Huntington's disease. Cell Cycle. 2007;6(23):2970-81.
10. Ratovitski T, Gucek M, Jiang H, Chighladze E, Waldron E, D'Ambola J, Hou Z, Liang Y, Poirer MA, Hirschhorn RR, Graham R, Hayden MR, Cole RN, Ross CA. Mutant Huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. Journal of Biological Chemistry. 2009;284:10855-67.
11. Schilling G, Klevytska A, Tebbenkamp AT, Juenemann K, Cooper J, Gonzales V, Slunt H, Poirer M, Ross CA, Borchelt DR. Characterization of huntingtin pathologic fragments in human Huntington disease: Transgenic mice, and cell models. J Neuropathol Exp Neurol. 2007;66(4):313-20. (Pubitemid 46559024)
12. Landles C, Sathasivam K, Weiss A, Woodman B, Moffitt H, Finkbeiner S, Sun B, Gafni J, Ellerby LM, TrottierY, Richards WG, Osmand A, Paganetti P, Bates GP. Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease. Journal of Biological Chemistry. 2010;285(12): 8808-23.
13. Tebbenkamp AT, Green C, Xu G, Denovan-Wright EM, Rising AC, Fromholt SE, Brown HH, Swing D, Mandel RJ, Tessarollo L, Borchelt DR. Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative. Hum Mol Genet. 2011;20(14):2770- 82.
14. Tebbenkamp AT, Crosby KW, Siemienski ZB, Brown HH, Golde TE, Borchelt DR. Analysis of proteolytic processes and enzymatic activities in the generation of huntingtin nterminal fragments in an HEK293 cell model. PLoS ONE. 2012;7(12):e50750.
15. Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, Dawson VL, Dawson TM, Ross CA. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet. 1998;7(5):783-90. (Pubitemid 28221240)
16. 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. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 1998;18(2):150-4. (Pubitemid 28082462)
17. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP. 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. (Pubitemid 26374323)
18. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR. Intranuclear inclusions and neuritic pathology in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999;8:397-407. (Pubitemid 29097327)
19. Tebbenkamp AT, Swing D, Tessarollo L, Borchelt DR. Premature death and neurologic abnormalities in transgenic mice expressing a mutant huntingtin exon-2 fragment. Hum Mol Genet. 2011;20(8):1633-42.
20. Waldron-Roby E, Ratovitski T, Wang X, Jiang M, Watkin E, Arbez N, Graham RK, Hayden MR, Hou Z, Mori S, Swing D, Pletnikov M, DuanW, Tessarollo L, Ross CA. Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin. J Neurosci. 2012;32(1):183-93.
21. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ, Li XJ, Simpson EM, Gutekunst CA, Leavitt BR, Hayden MR. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet. 2003;12(13):1555-67. (Pubitemid 36857303)
22. Gray M, Shirasaki DI, Cepeda C, Andre VM, Wilburn B, Lu XH, Tao J, Yamazaki I, Li SH, Sun YE, Li XJ, Levine MS, Yang XW. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci. 2008;28(24):6182-95.
23. Heng MY, Detloff PJ, Albin RL. Rodent genetic models of Huntington disease. Neurobiol Dis. 2008;32(1):1-9.
24. Woodman B, Butler R, Landles C, Lupton MK, Tse J, Hockly E, Moffitt H, Sathasivam K, Bates GP. The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Res Bull. 2007;72(2-3):83-97. (Pubitemid 46367466)
25. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature (London). 1970;227:680-5.
26. Dehay B, Weber C, Trottier Y, Bertolotti A. Mapping of the epitope of monoclonal antibody 2B4 to the proline-rich region of human Huntingtin: A region critical for aggregation and toxicity. Biotechnol J. 2007;2(5):559-64. (Pubitemid 46840044)
27. Wang CE, Zhou H, McGuire JR, Cerullo V, Lee B, Li SH, Li XJ. Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol. 2008;181(5):803-816. (Pubitemid 351786985)
28. Schilling G, Jinnah HA, Gonzales V, Coonfield ML, Kim Y, Wood JD, Price DL, Li XJ, Jenkins N, Copeland N, Moran T, Ross CA, Borchelt DR. Distinct behavioral and neuropathological abnormalities in transgenic mouse models of HD and DRPLA. Neurobiol Dis. 2001;8(3):405-18. (Pubitemid 32566132)
29. Sathasivam K, Neueder A, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RL, Roos RA, Howland D, Detloff PJ, Housman DE, Bates GP. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U.S.A. 2013;110(6): 2366-70.