The Annual Meeting of the Society for Neuroscience is the largest gathering of neuroscientists in the world with more than 29,000 scientists attending this year's meeting in San Diego, Calif., November 9-13. The meeting featured more than 100 new discoveries about ALS, generated in scores of laboratories around the world. The daily presentation of posters and plenary sessions announcing these new findings were well attended and provoked probing discussions among the many researchers worldwide dedicated to finding the causes and treatments for the disease. Many of the investigators presenting are either funded by The ALS Association or received prior research awards supporting earlier work leading to their current findings. In addition, both current and past Milton Safenowitz Post-Doctoral Fellows presented at the meeting. Links to the abstracts from several of these presentations are included below.
The Importance of Non-neuronal Cells
One major theme emerging from research presented at the meeting is the critical importance of non-neuronal cells in harming motor neurons. Neurons are surrounded by and supported by several types of non-neuronal cells, including astrocytes, oligodendrocytes and microglia. Research conducted several years back pointed the finger at astrocytes as contributors to ALS. That finding has been confirmed and extended by multiple groups, who presented work showing that even when a disease-causing gene is expressed only in one of these types of cells, motor neurons, are damaged.
Specifically, groups showed motor neurons are damaged when astrocytes express mutant FUS, astrocytes express mutant C9ORF72, astrocytes expressed mutant TDP-43, oligodendrocytes express mutant SOD1 (also shown by a second group), and when motor neurons are exposed to astrocytes from sporadic ALS patients.
The consistent message from these studies is that these non-neuronal cells are important to consider when developing therapies. If researchers can find the means by which they do their damage, it should be possible to develop therapies against them. One strong contender is a signaling molecule called NF-kappaB. One group showed that turning off NF-kappaB in microglia was protective in both cell culture and in ALS mice, suggesting that blocking it with a drug might be a valuable strategy to explore for therapy. This finding also highlights the potential importance of neuroinflammation in the ALS disease process. Inflammation is a normal immune response, but prolonged inflammation can harm tissue. Microglia are central players in the immune system of the brain and spinal cord, and they are believed to worsen the disease process when they become activated. Astrocytes can also contribute to this response, when they convert to “attack mode,” which they apparently do in ALS, according to one study presented.
The C9ORF72 Gene
New work also extended the understanding of the C9ORF72 gene, the most common cause of inherited ALS. The mutant gene contains a long repeated section, which forms the cellular messenger called RNA. This expanded RNA clumps together, which researchers believe may trap other molecules and disrupt cell function. Groups showed that RNA made from the expanded repeat mutation of the gene was toxic and that unusual proteins made from the repeat are also toxic to motor neurons. A recently published discovery, confirmed by a separate group at the meeting, is that two long strands of RNA are made from the gene, one the normal or “sense” strand and the other the “antisense” strand made from the opposite side of the DNA. The significance of this antisense strand is not yet known, but it may require therapy directed directly at it, along with therapy targeting the sense strand.
Potential Routes for Therapy
Multiple studies explored the potential for new therapies. These included a drug that helps proteins fold correctly and a drug that alters microglial activity, targeting mutant SOD1 protein with antibody-like molecules and gene therapy, and stem cells for drug testing and for therapy.
A key unmet need in ALS clinical trials is a way to quickly and objectively track response to therapy. A new study of biomarkers in blood and cerebrospinal fluid shows promise in meeting that need. A combination of measurements from these fluids, taken after disease onset, was highly predictive of disease duration. In a clinical trial setting, this type of measurement might be used to determine if a treatment had altered the predicted course of the disease.
“All of these studies demonstrate the extraordinary dedication of researchers throughout the world to understanding and combating ALS,” said Lucie Bruijn, Ph.D., Chief Scientist for the Association. “These studies, and many more like them, help us determine the shortest route to developing effective therapies.”