Abstract
We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of α-synuclein, amyloid β1–42 (Aβ1–42), and mouse prion protein. Moreover, PQQ-modified α-synuclein and a proteolytic fragment of the PQQ-modified α-synuclein are able to inhibit the amyloid formation of α-synuclein. Here, we identified the peptide sequences that play an important role as PQQ-modified specific peptide inhibitors of α-synuclein. We demonstrate that the PQQ-modified α-Syn36–46 peptide, which is a partial sequence of α-synuclein, prevented α-synuclein amyloid fibril formation but did not inhibit Aβ1–42 fibril formation. In addition, the α-synuclein partial peptide modified with other small-molecule inhibitors, Baicalein and epigallocatechin gallate (EGCG), prevented α-synuclein fibril formation. Currently reported quinone amyloid inhibitors do not have selectivity toward protein molecules. Therefore, our achievements provide a novel strategy for the development of targeted specific amyloid formation inhibitors: the combination of quinone compounds with specific peptide sequence from target proteins involved in amyloid formation.
Highlights
Conformational neurodegenerative diseases are characterized by the formation and accumulation of misfolded proteins or amyloid fibrils
We have reported that pyrroloquinoline quinone (PQQ) prevents the amyloid fibril formation of α-Syn, amyloid β1–42 (Aβ1–42) and mouse prion protein in vitro [21,22]
We demonstrate that the PQQ-modified α-Syn36–46 peptide, which is a partial sequence of α-Syn, prevented α-Syn amyloid fibril formation, but did not inhibit Aβ1–42 fibril formation
Summary
Conformational neurodegenerative diseases are characterized by the formation and accumulation of misfolded proteins or amyloid fibrils. We have reported that pyrroloquinoline quinone (PQQ) prevents the amyloid fibril formation of α-Syn, Aβ1–42 and mouse prion protein in vitro [21,22]. We recently reported that proteolytic-digested PQQ-modified α-Syn inhibits amyloid formation as effectively as the PQQ-modified α-Syn does [23] PQQ-modified α-Syn partial peptide inhibits amyloid formation by interacting with intact α-Syn, based on the specific molecular recognition. Based on the identified sequence information, we prepared the PQQ-modified α-Syn partial peptides, and investigated their ability to block amyloid formation inhibition using α-Syn and Aβ1–42. In addition to PQQ, the α-Syn partial peptide was modified using other small molecule inhibitors, Baicalein and EGCG, and their inhibitory effects on α-Syn fibril formation were evaluated
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