Title:Oxidative Stress and Neurodegenerative Diseases: A Neurotrophic Approach
Volume: 16
Issue: 1
Author(s): Carme Espinet, Hugo Gonzalo, Catherine Fleitas, Maria Jose Menal and Joaquim Egea
Affiliation:
Keywords:
Alzheimer's disease, antioxidants, apoptosis, neurodegeneration, oxidative stress, p75NTR, pro-NGF.
Abstract: Neurotrophins are important neurotrophic factors involved in the survival, differentiation and
function of a wide variety of neuron populations. A common feature for most neurotrophins is that they are
synthesized as precursor proteins (pro-neurotrophins) that upon being processed by proteolysis render the
mature active form responsible for most of their trophic functions. However, some of the pro-neurotrophin
form of these proteins, such as the precursor form of NGF (pro-NGF), have been shown to induce opposite effects and
trigger apoptosis on neurons through the p75NTR receptor. This suggests that the balance between the levels of proneurotrophin
and neurotrophin must be tightly controlled. In this context, it has been shown that in conditions of oxidative
stress due for instance to aging or the development of some neurodegenerative disease, neurotrophins are oxidatively
modified at least by advanced glycation/lipoxidation end products (AGE/ALEs) which makes pro-NGF refractary to be
processed. The lack of maturation and the imbalance in favor of the precursor form may change the pattern of active signaling
pathways towards cell death, thus exacerbating the deleterious alterations, for instance during the development of
neurodegenerative diseases. Besides that, AGE/ALEs also induce the processing of the pro-NGF receptor p75NTR by α-
secretase which is followed by the processing by γ -secretase and the release of the intracellular domain of p75NTR
(p75NTRICD). Once cleaved, p75NTRICD recruits two intracellular interactors, NRIF and TRAF6, which allows NRIF
phosphorylation by JNK. The phosphorylated form of NRIF then translocates to the nucleus and induces the expression of
pro-apoptotic proteins. In this chapter we will summarize the mechanisms by which ROS- induce protein modifications,
which proteins are susceptible to be modified, how these modifications affect function and signaling and, finally, how
they can be related to neurodegenerative diseases.
