Abstract

Cyclophilin D (CypD) is a peptidyl-prolyl isomerase expressed in the nucleus and transported into the mitochondria where it is best associated with the regulation of the mitochondrial permeability transition pore (MPTP). There are, however, other possible roles of CypD in the mitochondria which may or may not be linked with the MPTP. Alpha synuclein (αSyn) is shown here to interact directly with CypD via its acidic proline-rich C-terminus region and binding at the putative ligand binding pocket of CypD. The study shows that CypD binding with soluble αSyn prevents its aggregation. Furthermore, the addition of CypD to preformed αSyn fibrils leads to the disassembly of these fibrils. Enzymatically-compromised mutants of CypD show reduced abilities to dissociate αSyn aggregates, suggesting that fibril disassembly is linked to the increased rate of peptidyl-prolyl isomerisation catalysed by CypD. Protein aggregation in the mitochondria is increasingly seen as the cause of neurodegeneration. However, protein aggregation is a reversible process but disaggregation requires help from other proteins such as isomerases and chaperones. The results here demonstrate a possible mechanism by which CypD achieves this and suggest that disaggregation could be one of the many functions of this protein.

Highlights

  • Cyclophilin D (CypD) is a mitochondrial peptidyl-prolyl isomerase that has been implicated to be involved in the mechanisms of many diseases, it is best known as a regulator for the opening of the mitochondria permeability transition pore (MPTP)

  • Incubation of CypD with freshly prepared αSyn repressed the aggregation of αSyn, as assessed using Thioflavin T (ThT) fluorescence, over a period of 3 days compared with αSyn alone (Fig. 1a)

  • Exposure of preformed αSyn fibrils to CypD resulted in a change in fibril morphology, as observed by Transmission Electron Microscopy (TEM) (Fig. 1b)

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Summary

Introduction

Cyclophilin D (CypD) is a mitochondrial peptidyl-prolyl isomerase that has been implicated to be involved in the mechanisms of many diseases, it is best known as a regulator for the opening of the mitochondria permeability transition pore (MPTP). There is a correlation between αSyn entry into the mitochondria, reduced mitochondrial membrane potential (∆Ψm) and mitochondria dysfunction, implicating the involvement of the MPTP11,12 These effects of αSyn can be rescued by the addition of CsA, a CypD inhibitor, this could be through the role of CypD as a regulator of the MPTP rather than as a result of direct interaction between αSyn and CypD13. The acidic C-terminus region of αSyn is identified to be the main binding site to CypD These in vitro results provide some mechanistic insights into how and why isomerases dissociate protein aggregates

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