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Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...

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Detecting morphologically distinct oligomeric forms of alpha-synuclein.

Sharareh Emadi1, Srinath Kasturirangan, Min S Wang

  • 1Department of Chemical Engineering, Arizona State University, Tempe, Arizona 85287-6006, USA.

The Journal of Biological Chemistry
|January 15, 2009
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Researchers developed a novel antibody fragment that targets toxic alpha-synuclein aggregates. This discovery offers potential diagnostic and therapeutic strategies for Parkinson disease (PD) by specifically recognizing pathological forms in brain tissue.

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Immunology

Background:

  • Misfolding and aggregation of alpha-synuclein are strongly linked to Parkinson disease (PD) pathogenesis.
  • Oligomeric forms of alpha-synuclein are implicated as toxic species causing neurodegeneration.
  • The specific toxic oligomeric forms involved in PD and their roles remain unclear.

Purpose of the Study:

  • To identify and characterize novel reagents that specifically interact with toxic alpha-synuclein aggregates.
  • To develop tools for studying the role of different alpha-synuclein aggregate forms in PD.
  • To explore potential diagnostic and therapeutic agents for PD targeting alpha-synuclein.

Main Methods:

  • Isolation of a single chain antibody fragment (syn-10H scFv) using phage display.
  • Characterization of the binding specificity of syn-10H scFv to various alpha-synuclein oligomeric forms.
  • In vitro aggregation inhibition assays.
  • Assessment of syn-10H scFv's ability to block alpha-synuclein-induced toxicity in human neuroblastoma cell lines (SH-SY5Y).
  • Immunohistochemical analysis of PD and healthy human brain tissue.

Main Results:

  • A novel scFv (syn-10H scFv) was identified that binds to larger, later-stage alpha-synuclein oligomers.
  • Syn-10H scFv inhibits alpha-synuclein aggregation in vitro.
  • The antibody fragment blocks extracellular alpha-synuclein toxicity in SH-SY5Y cells.
  • Syn-10H scFv specifically recognizes naturally occurring alpha-synuclein aggregates in PD brain tissue, but not in healthy brain tissue.

Conclusions:

  • Syn-10H scFv is a potent inhibitor of alpha-synuclein aggregation and toxicity.
  • This antibody fragment specifically targets pathological alpha-synuclein aggregates found in Parkinson disease.
  • Syn-10H scFv represents a promising tool for PD research and a potential diagnostic and therapeutic candidate.