Neurotrophin regulation of neuronal death after injury

MONTROULL, LAURA; ROTHBARD, D; ZANIN, JUAN PABLO; LEVISON, S; FRIEDMAN, WILMA J.

Congreso; Neuroscience 2016; 2016

The neurotrophin family of growth factors regulates neuronal growth, differentiation and survival during development by activating signaling via the Trk family of receptor tyrosine kinases. However, the neurotrophin precursors, or proneurotrophins, are potent ligands for the p75 neurotrophin receptor (p75NTR)sortilin complex that can induce apoptosis, especially after injury.We have previously demonstrated that p75NTR is induced after injury induced either by seizures or by contusion in a model of traumatic brain injury. Moreover, blocking either the p75 receptor, or the proNGF ligand, can attenuate neuronal death. To test the hypothesis that p75NTR promotes secondary cell death, we provided a p75NTR siRNA intranasally immediately following a controlled cortical injury administered to adult C57/Bl/6 mice. Data obtained are in agreement with our previous findings that p75NTR KO mice demonstrated 2 fold fewer apoptotic neurons 3 DPI. Furthermore, knockdown of p75NTR improved overall neurological function and in particular improved sensorimotor performance on beam walking tests. In addition to promoting neuronal apoptosis, we are also investigating a role for p75NTR in regulating axonal degeneration, and determining whether this is independent of neuronal death, or part of a continuum leading to neuronal death. We are studying the mechanisms governing the process of neuronal apoptosis and axonal degeneration.We previously demonstrated that p75NTRmediated apoptotic signaling requires activation of the intrinsic caspase pathway, involving caspases9, 6 and 3, and simultaneous induction of PTEN to suppress Akt activation. ProNGF induction of PTEN occurred at the translational level, and we are currently investigating mechanisms by which this is regulated. We are also determining the effectiveness of inhibiting the receptor compared with preventing downstream signaling.