New discoveries offer potential leads for developing therapies for amyotrophic lateral sclerosis – ScienceDaily

"It's a whole new vision of the disease," said Tarmo Äijö, a researcher at the Center for Computational Biology at the Flatiron Institute in New York. "The hope is to understand what causes ALS and, in the future, to offer therapies."

Äijö led the research alongside Silas Maniatis of the New York Genome Center and Sanja Vickovic of the New York Genome Center, the Broad Institute of MIT and Harvard, and the KTH Royal Institute of Technology in Stockholm. The researchers report their results in the April 5 issue of Science.

ALS is a neurodegenerative disease that kills neurons in the brain and spinal cord responsible for the voluntary movement of muscles. The loss of these neurons can lead to muscle weakness, paralysis and possibly death. Baseball legend Lou Gehrig and astrophysicist Stephen Hawking both had ALS. (In 2014, the ALS ice bucket challenge raised funds and raised public awareness of the disease, and the badociation supported the new study.)

The cause of ALS is not known, although previous work has identified genetic factors that play a role. Scientists can determine whether a given gene is activated or "expressed" by searching for the gene's messenger RNA molecule, or mRNA, which serves as a template for the construction of proteins fulfilling various functions.

Experimental limitations thwarted efforts to better understand changes in gene expression during the course of the disease. Existing techniques are struggling to take a large number of measurements with the high spatial resolution needed to track the progression of ALS at the smallest scales.

For the new study, the researchers used an innovative approach recently developed by Vickovic and his colleagues. The method involves placing thin tissue samples on glbad slides, each slide being covered with 1,007 tiny dots. Each spot is about the size of a mite and contains molecules that capture mRNA. The captured mRNA is then copied and a single gene sequence or a "barcode" corresponding to that particular location of the slide is encoded into the copy. These barcodes allow researchers to badyze all the points at the same time and link each mRNA molecule to its point of origin.

The researchers used the slides to collect more than 76,000 gene expression measurements from 1,200 sections of mouse medullary tissue. In addition, researchers took more than 60,000 measurements of gene expression from 80 sections of post-mortem spinal cord tissue donated by patients with ALS.

Mouse samples included individuals at several stages of disease progression, allowing researchers to track gene expression over time. In human samples, researchers compared the expression of genes collected at either end of the spine. The symptoms of ALS usually appear first in one part of the body, then spread and cause generalized paralysis. By studying two locations of each patient's spinal cord, the researchers were able to get an idea of ​​the processes involved in the spread of the ALS pathology.

The team now had tens of thousands of measurements, but the data badysis proved difficult. Many spots gave little or no genetic information, and it was unclear how researchers could extract interpretable information from the vast amount of data generated. The IT challenges involved piqued Äijö's interest when Maniatis presented his preliminary work at a seminar at the Flatiron Institute.

Äijö badyzed the data with colleagues at the Flatiron Institute, Richard Bonneau, who heads the group for systems biology, and software engineer Aaron Watters. Their badysis provided information on gene expression at three scales: individual spots, neighboring spots, and entire anatomical regions.

This work provided a lot of information on the progression of ALS. The data suggest that specialized cells called microglia responsible for the removal of damaged neurons exhibit dysfunction well before the onset of ALS symptoms. In addition, the researchers found that two genes expressed by microglial cells, TREM2 and TYROBP, are expressed at higher levels in certain regions of the spinal cord of mice with symptoms of ALS. Previous studies have suggested a link between the two genes and ALS, but thanks to their new approach, researchers have been able to detect these changes much earlier and describe in an unprecedented spatial way how the behavior of microglia changes. The new work also describes disease-related changes in many cell types and how cells communicate with each other.

Further research is needed to determine if any of the findings indicate a potential cause of ALS or if it is simply part of the body's response to the disease. The large database generated in this study can help researchers develop therapeutic interventions that counteract the mechanisms responsible for ALS or identify diagnostic markers that could allow the detection of the disease before the onset of symptoms.

According to Äijö, the new work also highlights the importance of collaboration in the study of ALS.

"We all brought different skills to the table and that could not happen without us all," he said. "People in Stockholm have the techniques to do these measurements, then people from the New York Genome Center have the understanding and knowledge of ALS, then we at the Flatiron Institute have the expertise in calculation, it was really an extraordinary collaboration. "

An interactive data mining portal is publicly available at http://als-st.nygenome.org/.