Identification of Pin1 Isomerase on Neuronal Cell Rescue in Ischemic Brain Injury

Abstract

Pin1 contains two functional domains, an N‐terminal WW domain and a C‐terminal PPIase domain. The WW domain is a phosphorylation specific protein interaction module that directs Pin1 to its substrate‐proteins phosphorylated at certain serine or threonine residues followed by proline. Upon this binding, the PPIase domain catalyzes conformational change of the Pin1 substrates by isomerizing specific pSer/Thr‐Pro bonds; thus, we hypothesized that Pin1 can regulate neuronal cell death and neurogenesis through Pin1 inhibitor treatment after MCAo. To test the hypothesis, we elucidated roles of Pin1 following treatment of the Pin1 inhibitor at the sub‐acute phase after MCAo in rats. Juglone (1 mg/kg) was administered once a day for 7 days after MCAo. Histological and molecular analyses were used to determine apoptosis and neurodegeneration. MCAo+Jug leds to significant downregulation of Bcl‐2 and Bax the protein level compared with MCAo+veh (**p<.01). Ischemic brain injury promoted phosphorylation of Thr231 motif on tau as shown in Western blot. MCAo+Jug was shown to reduce the levels of Pin1 and tau5 in both Western blot and immunostaining (**p<.01). These results suggest that Pin1 isomerase acts as a pro‐apoptotic molecule in ischemic‐induced neuronal cell death after MCAo. Additionally, we suggest that Pin1 inhibition might alleviate the acceleration of apoptotic cell death from acute to sub‐acute after MCAo in rats.Funding: 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512