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In Silico and In Vitro Validation of Equine Alpha‐synuclein Misfolding Relevant to Pituitary Pars Intermedia Dysfunction
Author(s) -
Fortin Jessica,
Hetak Ashley,
Duggan Kelsey,
Penticoff Hailey
Publication year - 2021
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.2021.35.s1.00177
Subject(s) - alpha synuclein , colocalization , thioflavin , peptide , alpha (finance) , in silico , protein aggregation , biology , amino acid , microbiology and biotechnology , chemistry , biochemistry , parkinson's disease , medicine , pathology , disease , alzheimer's disease , gene , construct validity , nursing , patient satisfaction
Alpha‐synuclein is an abundant neuronal protein composed of 140 amino acids. Compelling evidence suggests that alpha‐synuclein can acquire a neurotoxic feature that kills dopamine secreting nerve cells in horses afflicted with Cushing's disease (known as pituitary pars intermedia dysfunction, PPID). Using bioinformatic analysis, we have identified that equine alpha‐synuclein has a high propensity to convert (misfold and aggregate) into this toxic form. While alpha‐synuclein is thought to play a pathogenic role in horses with equine PPID, it is unclear how alpha‐synuclein aggregates. We hypothesize that specific region(s) and/or amino acid variation(s) in equine alpha‐synuclein contribute to its misfolding. To test this hypothesis, we designed a bank of fragmented peptides to identify the region(s) most prone to aggregation. Bioinformatic analysis of equine alpha‐synuclein with Tango program indicated a similar propensity to aggregate as human alpha‐synuclein (Fig. 1). Region 62‐87 of the equine alpha‐synuclein peptide is the region most prone to aggregation according to Thioflavin T fluorescence assay. This fragment peptide 62‐87 is capable of generating mature fibrils as validated by electron microscopy. The discovery of the region responsible for equine alpha‐synuclein misfolding is relevant for the development of pharmacological agents that block the formation of alpha‐synuclein toxic aggregates.