Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2000 Mar 15;346(Pt 3):577–581.

alpha-synuclein overexpression promotes aggregation of mutant huntingtin.

R A Furlong 1, Y Narain 1, J Rankin 1, A Wyttenbach 1, D C Rubinsztein 1
PMCID: PMC1220887  PMID: 10698681

Abstract

Protein aggregates are a neuropathological feature of Huntington's disease and Parkinson's disease. Mutant huntingtin exon 1 with 72 CAG repeats fused to enhanced green fluorescent protein (EGFP) forms hyperfluorescent inclusions in PC12 cells. Inclusion formation is enhanced in cells co-transfected with EGFP-huntingtin-(CAG)(72) and alpha-synuclein, a major component of Parkinson's disease aggregates. However, alpha-synuclein does not form aggregates by itself, nor does it appear in huntingtin inclusions in vitro.

Full Text

The Full Text of this article is available as a PDF (143.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Conway K. A., Harper J. D., Lansbury P. T. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med. 1998 Nov;4(11):1318–1320. doi: 10.1038/3311. [DOI] [PubMed] [Google Scholar]
  2. Cooper J. K., Schilling G., Peters M. F., Herring W. J., Sharp A. H., Kaminsky Z., Masone J., Khan F. A., Delanoy M., Borchelt D. R. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet. 1998 May;7(5):783–790. doi: 10.1093/hmg/7.5.783. [DOI] [PubMed] [Google Scholar]
  3. Crowther R. A., Jakes R., Spillantini M. G., Goedert M. Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett. 1998 Oct 9;436(3):309–312. doi: 10.1016/s0014-5793(98)01146-6. [DOI] [PubMed] [Google Scholar]
  4. Cummings C. J., Mancini M. A., Antalffy B., DeFranco D. B., Orr H. T., Zoghbi H. Y. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet. 1998 Jun;19(2):148–154. doi: 10.1038/502. [DOI] [PubMed] [Google Scholar]
  5. DiFiglia M., Sapp E., Chase K. O., Davies S. W., Bates G. P., Vonsattel J. P., Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997 Sep 26;277(5334):1990–1993. doi: 10.1126/science.277.5334.1990. [DOI] [PubMed] [Google Scholar]
  6. El-Agnaf O. M., Jakes R., Curran M. D., Wallace A. Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson's disease. FEBS Lett. 1998 Nov 27;440(1-2):67–70. doi: 10.1016/s0014-5793(98)01419-7. [DOI] [PubMed] [Google Scholar]
  7. Engelender S., Kaminsky Z., Guo X., Sharp A. H., Amaravi R. K., Kleiderlein J. J., Margolis R. L., Troncoso J. C., Lanahan A. A., Worley P. F. Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet. 1999 May;22(1):110–114. doi: 10.1038/8820. [DOI] [PubMed] [Google Scholar]
  8. Fairley E. A., Kendrick-Jones J., Ellis J. A. The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. J Cell Sci. 1999 Aug;112(Pt 15):2571–2582. doi: 10.1242/jcs.112.15.2571. [DOI] [PubMed] [Google Scholar]
  9. Holmberg M., Duyckaerts C., Dürr A., Cancel G., Gourfinkel-An I., Damier P., Faucheux B., Trottier Y., Hirsch E. C., Agid Y. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet. 1998 May;7(5):913–918. doi: 10.1093/hmg/7.5.913. [DOI] [PubMed] [Google Scholar]
  10. Igarashi S., Koide R., Shimohata T., Yamada M., Hayashi Y., Takano H., Date H., Oyake M., Sato T., Sato A. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet. 1998 Feb;18(2):111–117. doi: 10.1038/ng0298-111. [DOI] [PubMed] [Google Scholar]
  11. Ii K., Ito H., Tanaka K., Hirano A. Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol. 1997 Feb;56(2):125–131. doi: 10.1097/00005072-199702000-00002. [DOI] [PubMed] [Google Scholar]
  12. Jenco J. M., Rawlingson A., Daniels B., Morris A. J. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. Biochemistry. 1998 Apr 7;37(14):4901–4909. doi: 10.1021/bi972776r. [DOI] [PubMed] [Google Scholar]
  13. Krüger R., Kuhn W., Müller T., Woitalla D., Graeber M., Kösel S., Przuntek H., Epplen J. T., Schöls L., Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998 Feb;18(2):106–108. doi: 10.1038/ng0298-106. [DOI] [PubMed] [Google Scholar]
  14. Li M., Miwa S., Kobayashi Y., Merry D. E., Yamamoto M., Tanaka F., Doyu M., Hashizume Y., Fischbeck K. H., Sobue G. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 1998 Aug;44(2):249–254. doi: 10.1002/ana.410440216. [DOI] [PubMed] [Google Scholar]
  15. Lunkes A., Mandel J. L. A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet. 1998 Sep;7(9):1355–1361. doi: 10.1093/hmg/7.9.1355. [DOI] [PubMed] [Google Scholar]
  16. Mangiarini L., Sathasivam K., Seller M., Cozens B., Harper A., Hetherington C., Lawton M., Trottier Y., Lehrach H., Davies S. W. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996 Nov 1;87(3):493–506. doi: 10.1016/s0092-8674(00)81369-0. [DOI] [PubMed] [Google Scholar]
  17. Martindale D., Hackam A., Wieczorek A., Ellerby L., Wellington C., McCutcheon K., Singaraja R., Kazemi-Esfarjani P., Devon R., Kim S. U. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 1998 Feb;18(2):150–154. doi: 10.1038/ng0298-150. [DOI] [PubMed] [Google Scholar]
  18. Mezey E., Dehejia A., Harta G., Papp M. I., Polymeropoulos M. H., Brownstein M. J. Alpha synuclein in neurodegenerative disorders: murderer or accomplice? Nat Med. 1998 Jul;4(7):755–757. doi: 10.1038/nm0798-755. [DOI] [PubMed] [Google Scholar]
  19. Narain Y., Wyttenbach A., Rankin J., Furlong R. A., Rubinsztein D. C. A molecular investigation of true dominance in Huntington's disease. J Med Genet. 1999 Oct;36(10):739–746. doi: 10.1136/jmg.36.10.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Narhi L., Wood S. J., Steavenson S., Jiang Y., Wu G. M., Anafi D., Kaufman S. A., Martin F., Sitney K., Denis P. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J Biol Chem. 1999 Apr 2;274(14):9843–9846. doi: 10.1074/jbc.274.14.9843. [DOI] [PubMed] [Google Scholar]
  21. Ostrerova N., Petrucelli L., Farrer M., Mehta N., Choi P., Hardy J., Wolozin B. alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci. 1999 Jul 15;19(14):5782–5791. doi: 10.1523/JNEUROSCI.19-14-05782.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Paulson H. L., Perez M. K., Trottier Y., Trojanowski J. Q., Subramony S. H., Das S. S., Vig P., Mandel J. L., Fischbeck K. H., Pittman R. N. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997 Aug;19(2):333–344. doi: 10.1016/s0896-6273(00)80943-5. [DOI] [PubMed] [Google Scholar]
  23. Perutz M. F. Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem Sci. 1999 Feb;24(2):58–63. doi: 10.1016/s0968-0004(98)01350-4. [DOI] [PubMed] [Google Scholar]
  24. Polymeropoulos M. H., Lavedan C., Leroy E., Ide S. E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997 Jun 27;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  25. Schilling G., Becher M. W., Sharp A. H., Jinnah H. A., Duan K., Kotzuk J. A., Slunt H. H., Ratovitski T., Cooper J. K., Jenkins N. A. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999 Mar;8(3):397–407. doi: 10.1093/hmg/8.3.397. [DOI] [PubMed] [Google Scholar]
  26. Skinner P. J., Koshy B. T., Cummings C. J., Klement I. A., Helin K., Servadio A., Zoghbi H. Y., Orr H. T. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature. 1997 Oct 30;389(6654):971–974. doi: 10.1038/40153. [DOI] [PubMed] [Google Scholar]
  27. Spillantini M. G., Schmidt M. L., Lee V. M., Trojanowski J. Q., Jakes R., Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997 Aug 28;388(6645):839–840. doi: 10.1038/42166. [DOI] [PubMed] [Google Scholar]
  28. Uéda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., Otero D. A., Kondo J., Ihara Y., Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282–11286. doi: 10.1073/pnas.90.23.11282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Weinreb P. H., Zhen W., Poon A. W., Conway K. A., Lansbury P. T., Jr NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry. 1996 Oct 29;35(43):13709–13715. doi: 10.1021/bi961799n. [DOI] [PubMed] [Google Scholar]
  30. Yoshimoto M., Iwai A., Kang D., Otero D. A., Xia Y., Saitoh T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9141–9145. doi: 10.1073/pnas.92.20.9141. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES