The regulatory role of Pin1 in neuronal death

Abstract

Regulated cell death predominantly involves apoptosis, autophagy, and regulated necrosis. It is vital that we understand how key regulatory signals can control the process of cell death. Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein, thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved. However, we know very little about how Pin1-associated pathways might play a role in regulated cell death. In this paper, we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death. Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases, accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy, thereby exhibiting distinct effects, including both neurotoxic and neuroprotective effects. Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.

Keywords: Pin1; apoptosis; autophagy; calpain; central nervous system; necroptosis; necrosis; neurodegenerative diseases; neuron; regulated neuronal death.

Figure 1

Timeline of the milestones of Pin1-mediated neuronal death in neurodegenerative diseases. AD: Alzheimer’s disease; HD: Huntington’s disease; PD: Parkinson’s disease; Pin1: Prolyl cistrans isomerase NIMA-interacting 1; SCI: spinal cord injury; TBI: traumatic brain injury.

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.

Figure 3

The molecular mechanisms responsible for how Pin1 regulates RN and autophagy signaling pathways. In RN in brain ischemia and traumatic injury, Pin1 acts as an important down-regulator of DAPK1-induced excitotoxic necrosis. The overexpression of DAPK1 resulted in a strong and significant enhancement of necrotic neurodegeneration in postsynaptic neurons; this was mediated by CaMK activation and the excessive influx of ions into the neurons. The DAPK1-dependent necrosis of postsynaptic neurons can be triggered by an excessive influx of ions. In RN in retinal diseases, Pin1 activation, induced by activated ionotropic glutamate receptor-mediated CaMKII and CaMKII activation, was shown to inhibit and enhance calpain-2 activity; this activated AIF, ultimately resulting in neuronal RN. In autophagy in AD, the inhibition of Pin1 promotes GSK-3β expression by inhibiting proteasome and Akt activation, and stimulating cell death via autophagy, as shown by increased levels of LC3-II. AD: Alzheimer’s disease; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Aβ: β-amyloid peptide; CaM: calmodulin; CaMKII: calmodulin-dependent protein kinase II; CAST: calpastatin; GSK-3β: glycogen synthase kinase-3β; NMDA: N-methyl-D-aspartic acid receptor; NMDAR: NMDA receptor; Pin1: prolyl cistrans isomerase NIMA-interacting 1; RGCs: retinal ganglion cells; RN: regulated necrosis; tAIF: truncated apoptosis-induced factor.