Inhibition of Huntingtin Fibrillogenesis by Specific Antibodies and Small Molecules: Implications for Huntington's Disease Therapy

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2000 Jun 1

PMID 10829068

Citations 77

Authors

V Heiser

E Scherzinger

A Boeddrich

E Nordhoff

R Lurz

N Schugardt

H Lehrach

E E Wanker

Affiliations

Soon will be listed here.

Abstract

The accumulation of insoluble protein aggregates in intra and perinuclear inclusions is a hallmark of Huntington's disease (HD) and related glutamine-repeat disorders. A central question is whether protein aggregation plays a direct role in the pathogenesis of these neurodegenerative diseases. Here we show by using a filter retardation assay that the mAb 1C2, which specifically recognizes the elongated polyglutamine (polyQ) stretch in huntingtin, and the chemical compounds Congo red, thioflavine S, chrysamine G, and Direct fast yellow inhibit HD exon 1 protein aggregation in a dose-dependent manner. On the other hand, potential inhibitors of amyloid-beta formation such as thioflavine T, gossypol, melatonin, and rifampicin had little or no inhibitory effect on huntingtin aggregation in vitro. The results obtained by the filtration assay were confirmed by electron microscopy, SDS/PAGE, and MS. Furthermore, cell culture studies revealed that the Congo red dye at micromolar concentrations reduced the extent of HD exon 1 aggregation in transiently transfected COS cells. Together, these findings contribute to a better understanding of the mechanism of huntingtin fibrillogenesis in vitro and provide the basis for the development of new huntingtin aggregation inhibitors that may be effective in treating HD.

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References

Vonsattel J, Myers R, Stevens T, Ferrante R, BIRD E, Richardson Jr E . Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985; 44(6):559-77. DOI: 10.1097/00005072-198511000-00003. View

Wanker E, Scherzinger E, Heiser V, Sittler A, EICKHOFF H, Lehrach H . Membrane filter assay for detection of amyloid-like polyglutamine-containing protein aggregates. Methods Enzymol. 1999; 309:375-86. DOI: 10.1016/s0076-6879(99)09026-6. View

Guntern R, Bouras C, Hof P, Vallet P . An improved thioflavine S method for staining neurofibrillary tangles and senile plaques in Alzheimer's disease. Experientia. 1992; 48(1):8-10. DOI: 10.1007/BF01923594. View

Caughey B, Race R . Potent inhibition of scrapie-associated PrP accumulation by congo red. J Neurochem. 1992; 59(2):768-71. DOI: 10.1111/j.1471-4159.1992.tb09437.x. View

LeVine 3rd H . Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 1993; 2(3):404-10. PMC: 2142377. DOI: 10.1002/pro.5560020312. View

Perutz M, Johnson T, Suzuki M, Finch J . Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A. 1994; 91(12):5355-8. PMC: 43993. DOI: 10.1073/pnas.91.12.5355. View

Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G . Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature. 1995; 378(6555):403-6. DOI: 10.1038/378403a0. View

Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H . Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J Biol Chem. 1996; 271(12):6839-44. DOI: 10.1074/jbc.271.12.6839. View

Sittler A, Devys D, Weber C, Mandel J . Alternative splicing of exon 14 determines nuclear or cytoplasmic localisation of fmr1 protein isoforms. Hum Mol Genet. 1996; 5(1):95-102. DOI: 10.1093/hmg/5.1.95. View

10.

Miroy G, Lai Z, Lashuel H, Peterson S, Strang C, Kelly J . Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci U S A. 1996; 93(26):15051-6. PMC: 26354. DOI: 10.1073/pnas.93.26.15051. View

11.

Davies S, Turmaine M, Cozens B, DiFiglia M, Sharp A, Ross C . Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997; 90(3):537-48. DOI: 10.1016/s0092-8674(00)80513-9. View

12.

Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R . Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell. 1997; 90(3):549-58. DOI: 10.1016/s0092-8674(00)80514-0. View

13.

DiFiglia M, Sapp E, Chase K, Davies S, Bates G, Vonsattel J . Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997; 277(5334):1990-3. DOI: 10.1126/science.277.5334.1990. View

14.

Merry D, Kobayashi Y, Bailey C, Taye A, Fischbeck K . Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet. 1998; 7(4):693-701. DOI: 10.1093/hmg/7.4.693. View

15.

Pappolla M, Bozner P, Soto C, Shao H, Robakis N, Zagorski M . Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem. 1998; 273(13):7185-8. DOI: 10.1074/jbc.273.13.7185. View

16.

Cummings C, Mancini M, Antalffy B, DeFranco D, Orr H, Zoghbi H . Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet. 1998; 19(2):148-54. DOI: 10.1038/502. View

17.

Warrick J, Paulson H, Bui Q, Fischbeck K, Pittman R, Bonini N . Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell. 1998; 93(6):939-49. DOI: 10.1016/s0092-8674(00)81200-3. View

18.

Lunkes A, Mandel J . A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet. 1998; 7(9):1355-61. DOI: 10.1093/hmg/7.9.1355. View

19.

Sittler A, Walter S, Wedemeyer N, Hasenbank R, Scherzinger E, EICKHOFF H . SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell. 1998; 2(4):427-36. DOI: 10.1016/s1097-2765(00)80142-2. View

20.

Klunk W, Debnath M, Koros A, Pettegrew J . Chrysamine-G, a lipophilic analogue of Congo red, inhibits A beta-induced toxicity in PC12 cells. Life Sci. 1998; 63(20):1807-14. DOI: 10.1016/s0024-3205(98)00454-8. View