How true “social” proteins can hold information about the origin of Alzheimer’s
An international team of scientists led by the ESRF, the European Synchrotron, has discovered how ECSIT proteins regulate protein behavior related to the energy activity in mitochondria, which is largely under the influence of Alzheimer’s disease. Their findings are published today in Cemie Angewandte.
The origin of the most common form of Alzheimer’s disease, which accounts for 95% of cases, remains unclear despite decades of scientific studies. “Before we understand the epidemiology, we need to understand biology,” explained Montse Soler López, a scientist leading Alzheimer’s disease research at the ESRF. “The only thing we’re sure about is that the most common form of Alzheimer’s is linked to getting older,” she says.
So researchers have been focusing on parts of the body that decline dramatically with age. Neurons, for example, are long-lived cells, meaning they do not renew themselves like other cells. Neurons lodge mitochondria, called “cell powerhouses” because of their active role in generating energy in the body. Over time, mitochondria suffer from oxidative stress and this leads to their malfunction. It has recently been discovered that people with Alzheimer’s may have an accumulation of amyloids inside mitochondria (previously it was thought that amyloids were only outside the neurons). Montse Soler López is trying to find out if there is a link between mitochondrial dysfunction, the presence of amyloids and early disease symptoms. “We believe that mitochondria can occur 20 years before the person shows symptoms of the disease.”
The team at ESRF teamed up with scientists at the Institut de Biologie Structurale (CNRS, CEA, Université Grenoble Alpes), Grenoble Institut des Neurosciences and the European Molecular Biology Laboratory (EMBL) to study the proteins is involved in the respiratory center that allows mitochondria to generate energy. The way mitochondria work is as follows: first, “helper” centers form a respiratory complex, which then generates energy in the form of ATP. Soler López and her team focused on a protein called ECSIT, which is fundamental in the immune system and appears to “communicate socially” or interact with many proteins.
Using an ESRF cryo-electron microscope and a Small Angle X-ray Scattering at the BM29 beamline of the ESRF, the researchers were able to determine the role of ECSIT in mitochondrial activity. “We have found that ECSIT plays a major role in assembling the‘ helper ’center, which collects the respiratory center 1, the largest complex of the respiratory chain in the mitochondria. The ‘helper’ center contains a number of proteins, and we have found that ECSIT regulates the function of the proteins so that they do the work they need to do ”, explains Soler López.
One of these proteins is ACAD9. This is a protein that can work to oxidize fatty acids or to accumulate the respiratory complex. Soler López and her colleagues found that ECSIT shuts down the oxidative action so that the protein can focus on accumulating the respiratory center. “If ECSIT did not take action, it would be a lie, with proteins doing several things at the same time, so ECSIT is essential in most respiratory and therefore, in mitochondrial activity,” he said. i.
They also found that ECSIT is very sensitive to the presence of amyloids. “We believe that when the amyloids begin to appear in the mitochondria, ECSIT enters too much, pushing the respiratory apparatus to protect the mitochondria from the destructive attack. If uncontrolled the device is very capable of damaging and destroying the neuron.We are still studying this, it is the next step in our research “, concludes Soler López.
Giachin, G., et al, Cemie Angewandte, DOI: 10.1002 / anie.202011548 and 10.1002 / ange.202011548.
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Montserrat Soler Lopez,
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