Transthyretin has conformation-selective proteolytic activity against α-synuclein

Transthyretin (TTR) is a plasma protein known as a transporter of thyroxine and retinol but also can inhibit the formation of amyloid {beta}-peptide (A{beta}) fibrils and catalyze the proteolysis of apolipoprotein A-I and A{beta}. Here, recombinant TTR is shown to have proteolytic activity against specific conformations of -synuclein (aSyn), a protein that accumulates in intraneuronal inclusions characteristic of Parkinsons disease (PD). Our discovery stemmed from the observation of a marked decrease in aSyn aggregation in the presence of submicromolar concentrations of TTR. Using integrated biophysical techniques, including advanced microscopy and mass spectrometry, we found that aSyn aggregation is prevented due to the proteolytic cleavage of free aSyn by TTR, in a reaction that is slower for S-glutathionylated TTR and faster for TTR preparations containing vestigial amounts of [~]70 kDa TTR oligomers (oTTR). Interestingly, this proteolysis-trigger effect is not unique to oTTR since it can also be induced by Teflon and glass surfaces independently of which TTR preparation is tested. Our results indicate that a change in aSyn conformation must precede the proteolysis step. The proteolysis of misfolded aSyn emerges as a possible TTR function with implications for the understanding of different neurodegenerative disorders.