Nanomedicine: Nanotechnology, Biology and Medicine
Volume 4, Issue 4 , Pages 350-357, December 2008

Mechanism of alpha-synuclein oligomerization and membrane interaction: theoretical approach to unstructured proteins studies

  • Igor F. Tsigelny, PhD

      Affiliations

    • Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California
    • San Diego Supercomputer Center, University of California San Diego, La Jolla, California
    • Corresponding Author InformationCorresponding author. University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0444, USA.
    • ,
  • Yuriy Sharikov

      Affiliations

    • San Diego Supercomputer Center, University of California San Diego, La Jolla, California
    • ,
  • Mark A. Miller, PhD

      Affiliations

    • San Diego Supercomputer Center, University of California San Diego, La Jolla, California
    • ,
  • Eliezer Masliah, MD

      Affiliations

    • Departments of Neurosciences and Pathology, University of California San Diego, La Jolla, California, USA

Received 4 January 2008; accepted 5 May 2008. published online 22 July 2008.

Abstract 

Misfolding and oligomerization of unstructured proteins is involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease, Huntington's disease, and other neurodegenerative disorders. Elucidation of possible conformations of these proteins and their interactions with the membrane is necessary to understand the molecular mechanisms of neurodegeneration. We developed a strategy that makes it possible to elucidate the molecular mechanisms of α-synuclein aggregation—a key molecular event in the pathogenesis of PD. This strategy can be also useful for the study of other unstructured proteins involved in neurodegeneration. The results of these theoretical studies have been confirmed with biochemical and electrophysiological studies. Our studies provide insights into the molecular mechanism for PD initiation and progression, and provide a useful paradigm for identifying possible therapeutic interventions through computational modeling.

Key words: Unstructured proteins, Parkinson's disease, α-synuclein: Molecular dynamics

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 This work was supported by National Institutes of Health grants AG18440 and AG02074, and a US Department of Energy INCITE grant. The authors are also grateful to International Business Machines for funding under its Institutes of Innovation program and for computational support on its BlueGene computers at the San Diego Supercomputer Center and at the Argonne National Laboratory. Material written in this article does not have any commercial associations, current and within the past five years, that might pose a potential, perceived or real conflict of interest.

PII: S1549-9634(08)00087-7

doi:10.1016/j.nano.2008.05.005

Nanomedicine: Nanotechnology, Biology and Medicine
Volume 4, Issue 4 , Pages 350-357, December 2008

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