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.