Patrick's Science Page

Overproduction of cells followed by massive cell death is a common phenomenon in the development of the mammalian nervous system.  Neuronal cell death is also associated with the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and  stroke. The survival of sympathetic neurons, along with other types of neurons, are dependent upon limiting quantities of trophic factors. The removal of nerve growth factor (NGF) from cultured sympathetic neurons results in 50% neuronal death by 28 hours and almost complete neuronal death by 48 hours.  This in vitro cell death paradigm mimics what is observed during normal development in vivo.  Although NGF has been well established as a survival factor for sympathetic neurons, the mechanism of action is not well defined. Phosphorylation of specific tyrosine residues on the tyrosine kinase receptor TrkA, activates the phosphoinositide 3-kinase (PI 3-kinase)/Akt, PLCgamma, and Ras/MAP kinase pathways. Several groups have demonstrated in primary sympathetic neurons that the MAP kinase and PLCgamma signaling pathways are necessary for cell growth and differentiation but are not necessary for neuronal survival. In contrast, pharmacological and molecular inhibitors of the PI 3-kinase/Akt pathway produced a cell death in sympathetic neurons similar to NGF-withdrawal.

NGF also binds, with lower affinity relative to TrkA, the p75 neurotrophic receptor (p75NTR). Results from several groups suggest that in the presence of NGF, p75NTR activates a survival pathway that may involve the activation of NF-kB, whereas in either limiting amounts of NGF or the presence of other neurotrophins, p75NTR may activate the JNK/c-Jun death pathway. Activation of NF-kB has been shown in several cell types, including neurons, to be necessary for the prevention of apoptosis.  NF-kB transcription factors are a family of dimeric molecules, including NF-kB1 (p50/p105), NF-kB2 (p52/p100), RelA, RelB, and c-Rel. Regulation of NF-kB-dependent transcription occurs mainly via cytosolic retention by a family of inhibitory molecules known as IkB. Degradation of IkB releases dimeric NF-kB molecules that in turn translocate into the nucleus to evoke their response. More recently, evidence exists that link the PI 3-kinase/Akt pathway to the activation of NF-kB in several cell types. Currently, my interests are to determine how NF-kB regulates survival of sympathetic neurons and identifying the downstream targets of this family of transcription factors responsible for the survival of these neurons.

Note: Green is activating, red is inhibitory

Selected Articles and Reviews

Baldwin, A.S., Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649-683, 1996.

Beg, A.A. and Baltimore, D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.  Science 274:782-784, 1996.

Carter, B.D., Kaltschmidt, C., Kaltschmidt, B., Offenhauser, N., Bohm, M., Baeuerle, P.A., and Barde, Y.A. Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75.  Science 272:542-545, 1996.

Crowder, R.J. and Freeman, R.S. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J. Neurosci. 18:2933-2943, 1998.

Deckwerth, T.L. and Johnson, E.M., Jr. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor (NGF).  J. Cell Biol. 123:1207-1222, 1993.

Kaplan, D.R. and Miller, F.D. Signal transduction by the neurotrophin receptors. Curr. Opin. Cell Biol. 9:213-221, 1997.

Maggirwar, S.B., Sarmiere, P.D., Dewhurst, S., and Freeman, R.S. Nerve growth factor-dependent activation of NF-kB contributes to survival of sympathetic neurons. J. Neurosci. 18:10356-10365, 1998.

O'Neill, L.A. and Kaltschmidt, C. NF-kappa B: a crucial transcription factor for glial and neuronal cell function.  Trends Neurosci. 20:252-258, 1997.

Taglialatela, G., Robinson, R., and Perez-Polo, J.R. Inhibition of nuclear factor kappa B (NFkappaB) activity induces nerve growth factor-resistant apoptosis in PC12 cells.  J. Neurosci. Res. 47:155-162, 1997