Oxidative Stress and Neurodegenerative Diseases: A Neurotrophic Approach

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.

Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death

“…Previous reports have observed ROS overproduction to occur rapidly after neuronal dysfunction, an important pathway to recognize as these reactive species are involved in both necrotic and apoptotic cell death [38–40]. It is well known that mitochondria play a crucial role in sustaining the oxidation-reduction equilibrium [41, 42].…”

Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors

“…Trophic factor signaling has been widely explored in aging and neurodegenative diseases. Espinet and colleagues argue that the precursor proteins of neurotrophins [proneurotrophins] are implicated in the development of neurodegenerative diseases, as they play a role in the mechanisms related to neuron apoptosis [56]. These authors state that aging induced oxidative stress may enhance the expression of pro-neurotrophin forms, exacerbating its neurodegenerative effects.…”

Olive polyphenol effects in a mouse model of chronic ethanol addiction

“…Occasional exposure to alcohol is sufficient to induce an imbalance in the intracellular redox state and produce tissue damage. Some target tissues of ethanol intoxication are the brain and the liver, which show a high metabolic rate involving a large amount of oxygen consumption mainly required to regenerate the adenosine triphosphate (ATP) necessary to maintain the intracellular ion homeostasis and to allow cell survival [8]. However, the elevated oxygen consumption makes the tissue more susceptible to generate oxidative stress and ROS hyperproduction [8].…”