Dissemination
The Problem
One of Europe's most intractable problems is the fact that its population is ageing. Besides the implications that this has for the workforce and for the financing of Europe's social security and pension schemes, there is an obvious health-derived problem.
People's life spans have increased in Europe, and hence there has been a dramatic
increase in the prevalence of neurodegenerative diseases. Currently, the prevalence
of dementia within the population over the age of 65 is about 10-15%. Of these, about
50% is caused by Alzheimer disease, indicating that the prevalence of this disorder
within the population over 65 years-old is around 6%. Moreover, it has been estimated
that almost one half of the population over 85 will suffer dementia.
The left-hand side images show a normal brain, whereas the right-hand side one is a brain from a patient suffering from Alzhemir disease. The bottom images indicate, in red/yellow, the most metabolically active zones of the brain. From these images, it appears clear that the loss of neurons in Alzheimer disease is accompanied by the loss of metabolic function.
The Possible Causes
Among the possible causes of these diseases, oxidative stress is thougth to be a primary event leading to this problem. Oxidative stress means the rupture of the equilibrated balance between the formation of oxygen-derived toxic species by the body and the ability of cells to remove them. As a consequence of this, reactive oxygen species damage certain components of the body cells, but espcially the neurons because these are more vulnerable than others.
Reactive nitrogen species are produced similarly by the body after the formation
of nitric oxide, a free radical that has been relatively unknwon until the
end of the 80's. Nitric oxide is an important molecule in biological systems, including
the brain, where it plays essential functions, specially in memory. However, when
nitric oxide joints with an excess of reactive oxygen species, there is a synergistic
formation of nitrogen-oxygen-derived species that, is not removed appropriately,
can seriously damage cell components such as proteins, nucleic acids or lipids of
the cell plasma membrane.
Schematic representation ofthe synapsis, i.e. the place where one neurons establish a connection with other(s). The signal (electrical impulse) of the pre-synaptic neuron is transferred to the post-synaptic neurons by releasing glutamate, a neurotransmitter amino acid that activates specific receptors placed at the plasma membrane of the post-synaptic neuron. Once these receptors are activated, the signal is transducted by the formation of nitric oxide.
Abnormal intra- or extracellular accumulation of several proteins, such as ß-amyloid, a-synuclein or huntingtin, among others, trigger neurodegeneration too. However, the precise causes of the abnormal accumulation of these proteins are not fully-understood. In addition, reactive oxygen/nitrogen-derived species can trigger the accumulation of those proteins, thus pointing to oxidative stress as a critical component of the molecular pathways leading to neurodegeneration.
The Research Activities of Juan P. Bolaños' Group
As an attempt to mitigate the problems derived by the increasing prevalence of neurodegenerative diseases, the Research Group of Juan P. Bolanos is interested in contributing to elucidate the molecular mechanisms leading to neuronal cell death occurring in those neurodegenerative diseases.
In particular, we are investigating the following main research lines:
1. Molecular targets
of nitric oxide in the brain at the intracellular level.
In 1993, we observed that nitric oxide caused a damage at the subcellular level in brain cells. In particular, the organelle involved in the generation of cellular energy –the mitochondrion– was particularly vulnerable to the actions of nitric oxide. We –and others– observed that the interaction of nitric oxide with mitochondria occurred at the level of cytochrome c oxidase, a critical protein involved in the transfer of electrons that come from the nutrients to be converted into energy in the mitochondria. Now, we are investigating whether this interaction is a first part of a more complex regulation of neuronal functions during normal and abnormal situations.
(Left) The mitochondrion is a small intracellular organelle with two membranes. (Right) Schematic representation of the mitochondrial respiratory chain at the inner mitochondrial membrane. Electrons from reduced substrates (NADH or succinate) are transferred, through this chain, to oxygen. This process helps generating the so-called proton-motive force, which serves to synthesize ATP, i.e. the molecular currency of the cell.
2. Strategies focused
to mitigate the neurotoxic effects of reactive oxygen/nitrogen-derived species.
In 1995, we found that gluathione, a tripeptide (small protein –peptide– formed only by three amino acids) known to detoxify xenobiotics by the liver, played a relevant role at preventing the neurons against the damage caused by the excess of reactive nitrogen-derived species. Following to this observation, we are now investigating how to modulate, in cultured cells and in experimental animals, glutathione content in the brain, and thus to use them as models of neurodegenerative diseases focused to search for possible therapeutic strategies.
Neurons in culture are often used to mimick experimental situations useful for the identification of both molecular pathways of neurodegeneration and possible therapeutic strategies.
3. Roles of components of the cell division in neurodegeneration.
Recently, in collaboration with Sergio Moreno at the Cancer Research Institute (Salamanca) and Angeles Almeida at the University Hospital of Salamanca, we observed that the specific removal, in post-mitotic (not dividing) neurons of a protein (Cdh1) thought to be involved in the regulation of dividing cells, triggered neurodegeneration. This has raised the idea that components of the cell division machinery may play an important role at regulating other cell cycle-derived proteins in non-dividing cells such as neurons. We are currently investigating further on the complex regulation of these proteins as an attempt to find new possible targets against neurodegeneration.
(Left) Neurons in culture transfected with DNA expressing a gree-fluorescent protein (GFP). (Right) GFP-expressing neurons after a treatment that induced neurodegeneration, as depicetd by the blebbing of axons and cell soma.