Treating Disease Mutations at the Source: A New Paradigm of Treatment for Spinocerebellar Ataxias

A subset of spinocerebellar ataxias (SCAs) are caused by genes that contain an expansion of the polyglutamine (polyQ) tract of the mutated protein. These expansions can lead to the dysregulation of many other genes. While this gene dysregulation has been shown to lead to ultimately lead to patient phenotypes, recently, alternative splicing has been implicated as a presymptomatic marker of SCAs and other neurodegenerative diseases.

Alternative splicing is one way that a cell can increase the diversity of proteins that it produces. Genes consist of introns and exons. Exons are regions of a gene that can produce a protein. Introns are regions of a gene that separate the exons and are important for the regulation of the gene, however, they do not form the final protein. By altering where protein production starts or which exons are included in the protein, the cell can produce multiple proteins from one gene. The most common type of alternative splicing is called “exon skipping”, meaning that one of the exons in a gene is “skipped”, so it is not included in the production of a protein. While alternative splicing is a normal occurrence, in a disease state there can be novel alternative splicing events can arise that are not normally seen in a cell. This phenomenon is known to occur in several different neurodegenerative diseases and is known to contribute to the progression of these diseases. However, while it is known that alternative splicing exists in SCAs, very little is known about its contribution to the progression of the disease.

The authors of this paper sought to answer this question of how alternative splicing contributes to the progression of SCAs by comparing already existing data sets from RNA sequencing experiments involving various different mouse models of SCA 1, 3, and 7. RNA sequencing is the process of quantifying the expression of genes in the tissue that is sequenced. By looking at these data sets, the authors were able to determine the amount of alternative splicing that is occurring in each of the SCA mouse models.

The main focus of this paper was a form of alternative splicing called exon skipping., This is the form of alternative splicing that has been found to cause the most damage in disease. After looking at exon skipping events in all of the datasets, the authors found that exon skipping was common across all SCA types and models looked at in the datasets before symptoms started occurring., Skipping events stayed consistent throughout the progression of the disease. Then, exon skipping was looked at specifically in pathways that are known to be affected during SCA. Similarly, the authors saw that exon skipping events occurred at similar rates between all SCA models, regardless of age and regardless of SCA type. It was also seen that these exon skipping events continued to occur in the same pathways throughout the age of the animals. This is important because this exon skipping occurs in the same genes throughout disease progression, giving a large time frame in which to potentially reverse this phenomenon and improve the disease.

To see if this exon splicing could be a potential target for disease treatments, the authors looked at more data sets with mouse models of SCA 1, 3, and 7.  In these data sets, the authors looked at experiments in which mice were treated with several different forms of treatment for SCA.  The authors shockingly found that exon skipping events decreased in disease-relevant pathways in all SCA types and mouse models, regardless of therapeutic treatment. This finding shows that the reduction of exon skipping could be important in improving symptoms and progression of SCA. This is important as treating exon skipping directly could also improve symptoms. Targeting exon skipping would stop dysfunctional proteins from being produced. Current treatments aim to lower the amount of dysfunctional protein being produced.

Overall, the authors established exon skipping as a disease-relevant phenomenon that occurs in several SCAs. They found that exon skipping occurs similarly as the disease progresses. This means that the severity of the disease or age does not seem to impact these exon skipping events. Changes even start before symptoms of SCA become visible. They also found that treatment of these SCAs leads to the reduction of these exon skipping events. This raises the important question of whether or not treating exon skipping events directly can improve disease progression. It also gives a strong basis for investigating exon skipping events as a potential mode of treatment for SCAs in the future.

Importantly, this discovery of exon skipping events in SCA is not dependent on the age or severity of the disease. This means that any treatments given for exon skipping can be administered at any point, regardless of disease progression or age of the patient. This is different from any current SCA treatments that are dependent on disease severity. Possibly, this will mean a single treatment for SCA patients that is more accessible to more patients. Overall, this discovery presents an exciting new pathway for researching a potential new type of treatment for SCAs.