How highly ‘sociable’ 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 the ECSIT protein regulates protein behavior related to the energy activity in mitochondria, which is partly greatly affected by 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 in charge of Alzheimer’s disease research at the ESRF. “The only thing we’re sure of 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 signs 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 create respiratory centers, which then generate 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 are required to do, “explained 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 were not active, it would be a lie, with proteins doing several things at the same time, so ECSIT is essential in the entire respiratory center and therefore, in mitochondrial activity,” she adds.

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 equipment well it can be destructive and destroy the neuron.we are still studying this, it is the next step in our research, “concludes Soler López.