The Role of PIN1 in neuronal programmed cell death following trophic factor deprivation

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2014.In the developing nervous system, programmed cell death (PCD) is critical for shaping and refining appropriate neuronal connections present in adulthood. Although PCD is regulated by many extrinsic and intrinsic cues, the availability of target-derived neurotrophic factors is a major determinate of whether developing neurons live or die. In the mature nervous system, trophic factor deprivation can also occur as a consequence of injury and disease and in such cases directly contributes to the pathogenesis of major neurologic disorders. Recent evidence suggests that the prolyl isomerase PIN1 may function as a proapoptotic modulator of survival in developing neurons. Studies using nerve growth factor (NGF)-dependent sympathetic neurons and serum- and high potassium-maintained cerebellar granule neurons (CGNs) have revealed that overexpression of PIN1 promotes cell death in the presence of trophic factors. These same studies raised the possibility that PIN1 regulates the proapoptotic JUN N-terminal kinase (JNK)-JUN pathway in neurons following trophic factor deprivation. Here we investigated the effects of germline loss of Pin1 in trophic factor deprivation-induced neuronal death and tested the hypothesis that PIN1 acts to promote death by facilitating the activation of the JNK-JUN pathway. Loss of Pin1 reduces caspase-3 activation and cell death in sympathetic neurons deprived of NGF in vitro and partially suppresses PCD of sympathetic neurons in the superior cervical ganglia (SCG) in vivo. Disruption of Pin1 suppresses the accumulation of JUN protein including JNK phosphorylated-JUN in trophic factor-deprived sympathetic neurons and CGNs. Pin1 disruption also inhibits induction of Jun mRNA and that of several proapoptotic target genes of JUN in sympathetic neurons following NGF withdrawal. Co-IP experiments reveal that PIN1 interacts with all JNK isoforms in CGNs, and these interactions are enhanced following trophic factor withdrawal. In addition, loss of Pin1 reduces the induction of JNK kinase activity in CGNs following withdrawal of trophic support and the accumulation of phospho-JNK in the nuclei of NGF-deprived sympathetic neurons. Our results demonstrate that PIN1 potentiates neuronal cell death following trophic factor deprivation by ensuring proapoptotic nuclear accumulation of JNK and full activation of its intrinsic kinase activity