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SYNCHROTRON LIGHT UNVEILS NEW INSIGHTS ABOUT AMYOTROPHIC LATERAL SCLEROSIS (ALS)

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Synergetic combination of different imaging and spectroscopic synchrotron techniques performed in ALBA and APS (USA) has discovered new aspects about astrocytes cells of this neurodegenerative disease. Results, published in Analytical Chemistry, show significant differences between ALS and control astrocytes, including structural, chemical and macromolecular anomalies.

Cerdanyola del Vallès, 28th January 2019. Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that causes the degeneration and death of neurons that control voluntary muscles. Still today the causes of this disease are unknown in 90% of the cases. However, some of them are caused by the mutation of sod1 gene. This gene encodes an enzyme (SOD1) that is involved in cellular protection against oxidative stress. Mutations dramatically alter the biochemical properties of SOD1, in particular its metal binding affinity and its anti-oxidative activity levels. But it is still unknown how these mutations block the normal cell function and lead to death of motor neurons.

The ALBA Synchrotron, in collaboration with researchers from the University of Belgrade Pavle Andjus and Stefan Stamenković (who accomplished his PhD thesis using these results) and Vladan Lučić from Max Planck Institute of Biochemistry (Germany), has studied with synchrotron light techniques and classical biochemical laboratory approaches the cellular structural and biochemical changes of this gene mutation in a transgenic animal model of ALS. In particular, scientists have analysed astrocytes, one kind of brain cells that are key players in pathological processes of this disease.

The final goal of the study, published in Analytical Chemistry, is "to better understand the disease and to contribute to the development of biomarkers and future therapeutic strategies", according to Tanja Dučić, corresponding author of the study and scientist of the MIRAS beamline at the ALBA Synchrotron.

During the experiments, scientists combined three different synchrotron methods to find out structural, chemical and macromolecular alterations in ALS astrocytes in their native form. Findings show that ALS astrocytes presented large aggregates connected with lipids disorders and significant concentrations of copper, linked to oxidative stress. Importantly, these methods do not require different biological preparation and cells from the same culture can be observed by different methods in correlative or complementary mode.

Complementary synchrotron techniques to know the inside of cells

This experiment successfully combined multimodal imaging synchrotron techniques, taking the most of each of them to complement results and obtain a global understanding of ALS astrocytes. This has been the first experiment where primary cells (astrocytes) were grown at the ALBA bio-laboratory, and directly used at ALBA beamlines.

To visualise the structural changes inside cells, experiments were done at MISTRAL beamline of ALBA, devoted to soft X-ray microscopy. One of the advantages of this technique is that "cells are rapidly frozen so they keep close to their native state, not chemically treated or sliced, what can offer very valuable information about how they behave naturally", says Tanja Dučić. The same sample preparation technique from the same culture of the cells was used for parallel analysis at the APS Synchrotron. At MISTRAL, scientists found in ALS astrocytes the presence of large aggregates that contain a great amount of lipid membranes.

Also at the ALBA Synchrotron, researchers performed infrared microspectroscopy at the MIRAS beamline to analyse the distribution and composition of these lipid membranes. They found the position of the oxidative stress in the cells and also, by using the spectroscopic data, they discovered that a lack of choline was common in ALS astrocytes, what altogether can lead to oxidative stress.

Finally, in order to investigate the trace elements composition and correlation with other cellular structures of the same cells prepared at ALBA, scientists performed cryo X-ray fluorescence in APS Synchrotron (USA) together with Barry Lai. They found that copper concentration was significantly higher in ALS astrocytes that, together with a decrease in the number of mitochondria, and SOD1 enzyme malfunction can be responsible for the oxidative stress present in ALS cells.

ALS, no cure and no effective treatment

ALS is the 3rd neurodegenerative disease, after dementia and Parkinson. In Spain, there are more than 3,000 people with ELA and three new cases appear every day, according to the Spanish Society of Neurology.

ALS is part of a group of disorders known as motor neuron diseases. Motor neurons are nerve cells that provide communication and link the brain and the voluntary muscles. Most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. However, about 10 percent of people with ALS survive for 10 or more years. For example, this was the case of the scientist Stephen Hawking who lived with the disease for more than 50 years.

In summer 2014, the Ice Bucket challenge social media campaign raised enormous awareness of this disease with more than 17 million people posting videos online and $115 million in donations for the American ALS Association.

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Figure: Multimodal synchrotron radiation microscopy of intact astrocytes from the hSOD1 G93A rat model of amyotrophic lateral sclerosis by using the cryo visible light (bottom left side), the cryo- TXM (bottom middle and right side), the cryo-XRF (top right side) and the FTIR microscopies (top left).

 IM_ALSExperimentMIRAS_IM1 IM_ALSExperimentBiolabIM2

Researchers Tanja Dučić and Stefan Stamenković during the experiment performed at ALBA, at the MIRAS beamline (left) and at the ALBA bio-lab (right).

Reference: Multimodal Synchrotron Radiation Microscopy of Intact Astrocytes from the hSOD1 G93A Rat Model of Amyotrophic Lateral Sclerosis. Tanja Dučić, Stefan Stamenković, Barry Lai, Pavle Andjus, and Vladan Lučić Analytical Chemistry 2019, 91, 2, 1460-1471