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Protein Disulfide Isomerase Can Reverse the Aggregation of α‐Synuclein
Author(s) -
Burress Helen,
Cilenti Lucia,
Serrano Albert,
Taylor Michael,
Tatulian Suren,
Teter Ken
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.814.6
Subject(s) - chemistry , neurodegeneration , fibril , protein aggregation , chaperone (clinical) , thioflavin , biophysics , protein folding , protein disulfide isomerase , biochemistry , enzyme , biology , alzheimer's disease , medicine , disease , pathology
Neurotoxic amyloid fibrils of α‐synuclein contribute to the etiology of Parkinson's disease. Protein disulfide isomerase (PDI) provides a protective effect against neurodegeneration that is linked to its chaperone function and its ability to disrupt protein aggregation. Here, we report PDI can both prevent and reverse the aggregation of α‐synuclein. Assays using Thioflavin T fluorescence or transmission electron microscopy demonstrated PDI can inhibit the formation of α‐synuclein fibrils when added at the onset of aggregation and can reverse fibrillization when added to intermediate fibrils 30 h after the initiation of aggregation. The chaperone but not oxidoreductase activity of PDI was required to disrupt α‐synuclein fibrillization. Biophysical studies found that substrate binding leads to the partial unfolding of PDI, which provides a possible molecular basis for the dissolution of α‐synuclein fibrils: the structural expansion of unfolded PDI could push against two or more proteins in the fibril, thus acting as a wedge to displace individual proteins from the aggregate. These data establish a new functional property for the chaperone activity of PDI that may explain how it protects against neurodegeneration.