Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson's disease pathogenesis and therapies - PubMed (original) (raw)

Review

Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson's disease pathogenesis and therapies

Abid Oueslati et al. Prog Brain Res. 2010.

Abstract

A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson's disease (PD) is essential for developing effective diagnostic, preventative and therapeutic strategies to treat this devastating disease. A number of post-translational modifications to alpha-syn are present within the Lewy bodies in the brains of affected patients and transgenic models of PD and related disorders. However, whether disease-associated alpha-syn post-translational modifications promote or inhibit alpha-syn aggregation and neurotoxicity in vivo remains unknown. Herein, we summarize and discuss the major disease-associated post-translational modifications (phosphorylation, truncation and ubiquitination) and present our current understanding of the effect of these modifications on alpha-syn aggregation and toxicity. Elucidating the molecular mechanisms underlying post-translation modifications of alpha-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease. Furthermore, the identification of the natural enzymes involved in regulating the post-translational modifications of alpha-synuclein will yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies.

2010 Elsevier B.V. All rights reserved.

PubMed Disclaimer

Similar articles

• α-Synuclein aggregation and modulating factors.
  Paleologou KE, El-Agnaf OM. Paleologou KE, et al. Subcell Biochem. 2012;65:109-64. doi: 10.1007/978-94-007-5416-4_6. Subcell Biochem. 2012. PMID: 23225002 Review.
• Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery.
  Lee VM, Trojanowski JQ. Lee VM, et al. Neuron. 2006 Oct 5;52(1):33-8. doi: 10.1016/j.neuron.2006.09.026. Neuron. 2006. PMID: 17015225 Review.
• Aggregation of alpha-synuclein in the pathogenesis of Parkinson's disease.
  Iwatsubo T. Iwatsubo T. J Neurol. 2003 Oct;250 Suppl 3:III11-4. doi: 10.1007/s00415-003-1303-x. J Neurol. 2003. PMID: 14579119
• The role of ubiquitin linkages on alpha-synuclein induced-toxicity in a Drosophila model of Parkinson's disease.
  Lee FK, Wong AK, Lee YW, Wan OW, Chan HY, Chung KK. Lee FK, et al. J Neurochem. 2009 Jul;110(1):208-19. doi: 10.1111/j.1471-4159.2009.06124.x. Epub 2009 Apr 27. J Neurochem. 2009. PMID: 19457126
• alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease.
  Lo Bianco C, Ridet JL, Schneider BL, Deglon N, Aebischer P. Lo Bianco C, et al. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10813-8. doi: 10.1073/pnas.152339799. Epub 2002 Jul 16. Proc Natl Acad Sci U S A. 2002. PMID: 12122208 Free PMC article.

Cited by

• In Search of Effective Treatments Targeting α-Synuclein Toxicity in Synucleinopathies: Pros and Cons.
  Fouka M, Mavroeidi P, Tsaka G, Xilouri M. Fouka M, et al. Front Cell Dev Biol. 2020 Sep 4;8:559791. doi: 10.3389/fcell.2020.559791. eCollection 2020. Front Cell Dev Biol. 2020. PMID: 33015057 Free PMC article. Review.
• Pathogenesis of α-Synuclein in Parkinson's Disease: From a Neuron-Glia Crosstalk Perspective.
  Yi S, Wang L, Wang H, Ho MS, Zhang S. Yi S, et al. Int J Mol Sci. 2022 Nov 25;23(23):14753. doi: 10.3390/ijms232314753. Int J Mol Sci. 2022. PMID: 36499080 Free PMC article. Review.
• Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy.
  Guerrero-Ferreira R, Taylor NM, Arteni AA, Kumari P, Mona D, Ringler P, Britschgi M, Lauer ME, Makky A, Verasdonck J, Riek R, Melki R, Meier BH, Böckmann A, Bousset L, Stahlberg H. Guerrero-Ferreira R, et al. Elife. 2019 Dec 9;8:e48907. doi: 10.7554/eLife.48907. Elife. 2019. PMID: 31815671 Free PMC article.
• Glycation modulates glutamatergic signaling and exacerbates Parkinson's disease-like phenotypes.
  Chegão A, Guarda M, Alexandre BM, Shvachiy L, Temido-Ferreira M, Marques-Morgado I, Fernandes Gomes B, Matthiesen R, Lopes LV, Florindo PR, Gomes RA, Gomes-Alves P, Coelho JE, Outeiro TF, Vicente Miranda H. Chegão A, et al. NPJ Parkinsons Dis. 2022 Apr 25;8(1):51. doi: 10.1038/s41531-022-00314-x. NPJ Parkinsons Dis. 2022. PMID: 35468899 Free PMC article.
• Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity.
  Soste M, Charmpi K, Lampert F, Gerez JA, van Oostrum M, Malinovska L, Boersema PJ, Prymaczok NC, Riek R, Peter M, Vanni S, Beyer A, Picotti P. Soste M, et al. Cell Syst. 2019 Sep 25;9(3):309-320.e8. doi: 10.1016/j.cels.2019.07.010. Epub 2019 Sep 11. Cell Syst. 2019. PMID: 31521608 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Medical

  • MedlinePlus Health Information

• Molecular Biology Databases

  • FlyBase

• Miscellaneous

  • NCI CPTAC Assay Portal