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Objective: Progressive accumulation of α-synuclein (α-syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which α-syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed

Objective: Progressive accumulation of α-synuclein (α-syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which α-syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing α-syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing antibodies that recognize both monomeric and higher molecular weight α-syn. In this context, the main objective of this study was to investigate the efficacy of immunotherapy with single-chain antibodies (scFVs) against specific conformational forms of α-syn fused to a novel brain penetrating sequence.

Method: We screened various scFVs against α-syn expressed from lentiviral vectors by intracerebral injections in an α-syn tg model. The most effective scFVs were fused to the cell-penetrating peptide penetratin to enhance transport across the blood–brain barrier, and lentiviral vectors were constructed and tested for efficacy following systemic delivery intraperitoneal into α-syn tg mice.

Result: Two scFVs (D5 and 10H) selectively targeted different α-syn oligomers and reduced the accumulation of α-syn and ameliorated functional deficits when delivered late in disease development; however, only one of the antibodies (D5) was also effective when delivered early in disease development. These scFVs were also utilized in an enzyme-linked immunosorbent assay (ELISA) assay to monitor the effects of immunotherapy on α-syn oligomers in brain and plasma.

Interpretation: The design and targeting of antibodies for specific species of α-syn oligomers is crucial for therapeutic immunotherapy and might be of relevance for the treatment of Lewy body disease.

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    Title
    • α-Synuclein Conformational Antibodies Fused to Penetratin Are Effective in Models of Lewy Body Disease
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    Date Created
    2016-06-16
    Resource Type
  • Text
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    Identifier
    • Digital object identifier: 10.1002/acn3.321
    • Identifier Type
      International standard serial number
      Identifier Value
      2328-9503
    Note
    • The final version of this article, as published in Annals of Clinical and Translational Neurology, can be viewed online at: http://onlinelibrary.wiley.com/wol1/doi/10.1002/acn3.321/abstract

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    This is a suggested citation. Consult the appropriate style guide for specific citation guidelines.

    Spencer, B., Williams, S., Rockenstein, E., Valera, E., Xin, W., Mante, M., . . . Sierks, M. R. (2016). α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease. Annals of Clinical and Translational Neurology, 3(8), 588-606. doi:10.1002/acn3.321

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