Prolyl-isomerase Pin1 accumulates in Lewy bodies of Parkinson Disease and facilitates formation of α-synuclein inclusions

Abstract

Parkinson disease (PD) is a relatively common neurodegenerative disorder that is characterized by the loss of dopaminergic neurons and by the formation of Lewy bodies (LBs), which are cytoplasmic inclusions containing aggregates of α-synuclein. Although certain post-translational modifications of α-synuclein and its related proteins are implicated in the genesis of LBs, the specific molecular mechanisms that both regulate these processes and initiate subsequent inclusion body formation are not yet well understood. We demonstrate in our current study, however, that the prolyl-isomerase Pin1 localizes to the LBs in PD brain tissue and thereby enhances the formation of α-synuclein immunoreactive inclusions. Immunohistochemical analysis of brain tissue from PD patients revealed that Pin1 localizes to 50-60% of the LBs that show an intense halo pattern resembling that of α-synuclein. By utilizing a cellular model of α-synuclein aggregation, we also demonstrate that, whereas Pin1 overexpression facilitates the formation of α-synuclein inclusions, dominant-negative Pin1 expression significantly suppresses this process. Consistent with these observations, Pin1 overexpression enhances the protein half-life and insolubility of α-synuclein. Finally, we show that Pin1 binds synphilin-1, an α-synuclein partner, via its Ser-211-Pro and Ser-215-Pro motifs, and enhances its interaction with α-synuclein, thus likely facilitating the formation of α-synuclein inclusions. These results indicate that Pin1-mediated prolyl-isomerization plays a pivotal role in a post-translational modification pathway for α-synuclein aggregation and in the resultant Lewy body formations in PD. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.