Breakthrough in the battle against neurodegenerative disease

New genomic research could shed light on the cause of two life-limiting neurodegenerative conditions and provide targets for potential therapies and treatments

Amyotrophic lateral sclerosis (ALS), commonly known as motor neurone disease, causes nerve cells in the brain and spinal cord to degenerate over time, leading to problems with movement. There is no cure, and currently no effective treatment.

Frontotemporal dementia (FTD) is a closely-related neurodegenerative condition, where behaviour and language are affected. Around 20% of ALS patients develop FTD, and the two conditions can overlap in their symptoms and progression.

Treatment options for ALS and FTD have been limited to date, but recent genomics research has opened up a new avenue for drug development.

The significance of RNA repeats

The most common cause of ALS is a variant in the C9orf72 gene, present in around 10% of ALS patients. The disease-causing variant contains an expansion of the repeating portion of the gene: a sequence of six base pairs that is repeated many times. The same variant is implicated in FTD.

Two new studies have contributed to an understanding of the pathways by which this variant causes disease, identifying targets for potential therapies.

Since the discovery of the C9orf72 variant, many studies have focused on the accumulation of RNA molecules in the cells. RNA molecules that include the repeat expansion appear to build up in the cell, causing large quantities of non-functional protein to be manufactured. The build-up of these proteins to toxic levels within the cell are believed to be the main cause of disease symptoms.

As a result, a great deal of research has focused on reducing the levels of these products inside cells, using approaches such as antisense oligonucleotides – small nucleotide sequences that bind to C9orf72 mRNA molecules containing the repeat and cause the cell to destroy them. This approach has shown promise in the laboratory, and a clinical trial is now taking place.

However, new research has suggested that the mechanism used by the cell to get rid of unwanted RNA is itself inhibited by the variant C9orf72 protein. The RNA exosome complex is part of the cellular machinery, and is responsible for degrading RNA molecules. A key protein in the exosome, EXOSC10, is crucial to maintaining this function. However, the researchers discovered that the small proteins made when the repeats were transcribed and translated impair the activity of EXOSC10, which may explain why the toxic RNA molecules and proteins accumulate.

Heightened immune responses

As well as the build-up of RNA molecules and proteins, cells carrying the expanded gene variant produce fewer normal C9orf72 products, although the impact of this is not fully understood. A recent study published in Nature investigates this, searching for a potential link between reduced levels of C9orf72 protein and related autoimmune disease.

Using samples from people with ALS as well as mouse models, the researchers showed that healthy C9orf72 protein has an immunological function.

First, they were able to show that levels of normal C9orf72 protein were indeed lower in blood and brain tissue samples taken from ALS patients, and that these cells showed a heightened immune response in patients with the expanded variant and FTD, compared with samples from patients with other types of ALS.

Next, experiments in mice showed that when normal C9orf72 protein is absent in myelocytes (a type of cell crucial to immune function), the levels of mRNA-encoding type I interferon-β protein are much higher. RNA sequencing of human cells from ALS patients showed enhanced interferon I activity.

Suppressing the STING

Interferons are an important part of the innate immune response to viruses, but overproduction is associated with autoimmune diseases and inflammation. Interferon production is stimulated by the ‘stimulator of interferon genes’ (STING) protein, part of the pathway that detects double-stranded DNA in the cell and is critical in the detection of viral infection.

The researchers also showed that normal C9orf72 protein is part of a regulatory pathway through which STING is regulated. When the cell produces the expanded variant, STING protein is not degraded in the cell, leading to an increased type I interferon response.

By inhibiting STING in cells lacking C9orf72, the researchers found that normal interferon responses and spleen sizes were restored in the mice, therefore identifying STING as a potential therapeutic target.

The researchers hope that inhibiting STING with a drug could decrease the risk of autoimmune disease in people with ALS. Inhibitory molecules do exist, and are at a pre-clinical stage of testing.