ECSIT protein can shed light on the origin of Alzheimer's disease

Headed by the European Synchrotron Radiation Facility (ESRF), an international research team has found how the ECSIT protein governs the behavior of proteins associated with the energy activity in mitochondria, which is most impacted in Alzheimer's disease. The study results were recently published in the Angewandte Chemie journal.

ECSIT protein can shed light on the origin of Alzheimer
Using the ESRF cryo-electron microscope and Small Angle X-ray Scattering at the ESRF's beamline BM29, the researchers managed to decipher the role of ECSIT in mitochondrial activity. Image Credit: European Synchrotron Radiation Facility/Stef Candé.

Despite years of scientific analyses, scientists were clueless about the origin of the most common form of Alzheimer’s disease, which is responsible for 95% of cases.

Before understanding the pathology, we need to understand the biology. The only thing we are sure about is that the most common form of Alzheimer’s is linked with ageing.”

Montse Soler López, Scientist, European Synchrotron Radiation Facility

Soler López is heading the research on Alzheimer’s disease at the ESRF.

As a result, scientists have been targeting the body parts that deteriorate significantly with age. For instance, neurons are nerve cells that last for a long time, which means that they do not regenerate themselves like how other cells do.

These nerve cells lodge mitochondria, which are said to be the “powerhouse of cells” due to their active role in producing energy in the body. And with time, mitochondria undergo oxidative stress, and this results in their malfunction.

Recently, it was found that in Alzheimer’s patients, amyloids might be accumulated within mitochondria (earlier it was believed that amyloids existed only outside the neurons).

Montse Soler López is attempting to find out whether there is a correlation between the presence of amyloids, mitochondrial dysfunction, and early symptoms of the disease.

According to Soler López, “We believe that malfunctioning of the mitochondria can take place 20 years before the person shows symptoms of the disease”.

The ESRF team collaborated with investigators from the Institut de Biologie Structurale (CNRS, CEA, and Université Grenoble Alpes), Grenoble Institut des Neurosciences, and the European Molecular Biology Laboratory (EMBL) to investigate the proteins involved in the respiratory complex that enables mitochondria to produce energy.

The manner through which mitochondria function is as follows: initially, “helper” complexes produce respiratory complexes, which then produce energy in the ATP form. Soler López and her group targeted an ECSIT protein, which is crucial in the immune system and seems to interact or “socialize” with several proteins.

The team used the ESRF cryo-electron microscope and small-angle X-ray scattering at the ESRF’s beamline BM29 and managed to interpret the function of ECSIT in mitochondrial function by employing the

We’ve found that ECSIT plays a major role in assembling the ‘helper’ complex, which will assemble the respiratory complex 1, the biggest complex of the respiratory chain in the mitochondria. In the ‘helper’ complex there are several proteins, and we’ve discovered that ECSIT regulates the function of the proteins so that they do the job they are required to do.”

Montse Soler López, Scientist, European Synchrotron Radiation Facility

ACAD9 is one of these proteins. This protein can work to assemble the respiratory complex or to oxidize fatty acids. Soler López and her collaborators discovered that the ECSIT protein turns off the oxidizing process, allowing the protein to focus on organizing the respiratory complex.

If ECSIT didn’t take action, it would be a mess, with proteins doing several things at the same time, so ECSIT is actually crucial in the whole respiratory complex and hence, in mitochondrial activity.”

Montse Soler López, Scientist, European Synchrotron Radiation Facility

The team also observed that the ECSIT protein is extremely sensitive to the presence of amyloids.

We think that when the amyloids start appearing in the mitochondria, ECSIT goes into overdrive, pushing the respiration mechanism to protect the mitochondria from the damaging invasion. If the mechanism is not well controlled it can become destructive and end up destroying the neuron. But we are still investigating this, it is the next step in our research,” concluded Soler López.

Video Credit: European Synchrotron Radiation Facility.

Source:
Journal reference:

Giachin, G., et al. (2020) Assembly of the mitochondrial Complex I assembly complex suggests a regulatory role for deflavination. Angewandte Chemie. doi.org/10.1002/anie.202011548.

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