Figure 2.

The molecular mechanisms underlying Pin1-regulated apoptosis signaling pathways.

In AD, reduced levels of Pin1 inhibits GSK-3β enzymatic activity; this could inhibit HIF-1 protein degradation and contribute to the expression of the cis isoform of pT668-APP. Next, the increased production of Aβ accelerates the formation of the cis isoform of pT231-Tau, finally promoting the progression of AD. Furthermore, caspase-3 can be activated by the accumulation of Aβ and promotes the formation of the cis isoform of pT231-Tau. In TBI, increased levels of DAPK1 inhibits Pin1 and then promotes the transformation of cis pT231-Tau as well as TBI. In PD, the overexpression of Pin1 facilitates the formation and stability of α-synuclein aggregation and promotes caspase-3 activation, finally leading to PD. In HD, Htt directly increases the activation of p53 and Pin1. Pin1 also interacts with p53 and triggers dissociation from its inhibitor iASPP. In addition, the overexpression of Pin1 leads to a reduction of Htt accumulation via UPS-mediated degradation. In stroke, increased levels of Pin1 promotes the stability of NICD by inhibiting FBW7-mediated poly-ubiquitination, up-regulates p53 transactivation, and enhances the production of ROS. In SCI, Pin1 promotes the degradation of Daxx and then activates the ASK1/JNK signaling pathway; this could promote Mcl-1 degradation and Bcl-2 inhibition. Pin1 also binds with and mediates a conformational change in pSer65-BIM_EL to protect pS65-BIM_EL from proteasomal degradation, finally leading to neuronal apoptosis. In epilepsy, the deletion of Pin1 enhanced AMPA and NMDA receptors by phosphorylating CaMKII, finally inducing excitotoxic neuronal death. In age-related neurodegeneration, Pin1 is progressively associated with lipofuscin, thus resulting in the generation of ROS; this process can be deleterious to neurons. AD: Alzheimer’s disease; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; APP: amyloid precursor protein; ASK1: apoptosis signal-regulating kinase 1; Aβ: β-amyloid peptide; BAX: Bcl-2-associated X; Bcl-2: B-cell lymphoma 2; BIM_EL: Bcl-2-interacting mediator of cell death, extra long; CaMKII: calmodulin-dependent protein kinase II; cyt C: cytochrome C; DAPK1: death-associated protein kinase 1; Daxx: death domain associated protein; FBW7: F-box and WD repeat domain containing domain protein 7; GSK-3β: glycogen synthase kinase-3β; HD: Huntington’s disease; HIF-1: hypoxia-inducible transcription factor-1; Htt: Huntingtin; iASPP: inhibitor of apoptosis-stimulating protein of p53; JNK: C-Jun N-terminal kinase; Mcl-1: myeloid cell leukemia sequence-1; NICD1: Notch intracellular domain 1; NMDA: N-methyl-D-aspartic acid receptor; PD: Parkinson’s disease; Pin1: prolyl cistrans isomerase NIMA-interacting 1; SCI: spinal cord injury; TBI: traumatic brain injury; UPS: ubiquitin-proteasome system.