Written by Dr. Carolyn J. Adamski Edited by Dr. Judit M Perez Ortiz

A research group uncovers a drug target to potentially correct motor phenotypes across several cerebellar ataxias.

When someone is diagnosed with spinocerebellar ataxia (SCA), their symptoms may look very similar despite the fact that different genes are causing the disease. There are over 35 genes known to cause cerebellar ataxia, each of which are studied by scientists to try to understand the ways in which they can each lead to disease. Increasingly, scientists are beginning to appreciate that perhaps it would be helpful to find commonalities between the different SCAs to identify treatment options that could help more SCA patients. The emerging picture is that the genes causing cerebellar ataxia are all vital to the health and function of neurons. Studies like these are currently being conducted all over the world. One group focused on MTSS1, a critical component of neuronal function. They made the exciting discovery that a handful of other genes known to cause cerebellar ataxia were doing so, at least in part, through MTSS1. This study uncovered a common network between cerebellar ataxia genes. Their hope is that someday clinicians will be able to treat many cerebellar ataxias with one therapy.

One approach scientists use to understand a gene’s function is to remove it from the genome, typically in mice, and observe what happens. This group reported that when they removed MTSS1, mice were not able to walk as well as healthy mice. This defect got progressively worse with age. What they observed in these mice looked very similar to what patients with cerebellar ataxia experience. Because there are a few areas of the brain important for walking, the authors wanted to make sure this was due to defects in the cerebellum. Neurons in the cerebellum missing MTSS1 were there, but they were unable to effectively communicate with other neurons in the brain and were slowly dying. When a neuron in the cerebellum fails to communicate the right message, things like poor coordination of body movement happen.

After establishing that removal of MTSS1 causes disease, this group went back to the literature and found that MTSS1 was a fundamental regulator of a pathway known to be critical for communication between neurons. They looked in the mice lacking MTSS1 and found that this pathway was abnormally in “overdrive”. They immediately started looking for ways to correct this. They hoped that by correcting this major pathway, they could help the neurons to more effectively communicate body movements again. Eventually, they found a compound that could specifically dial this pathway down. They gave this drug to the mice lacking MTSS1 and used a number of tests to examine their every movement. To their surprise, they were unable to tell the difference between normal healthy mice and those lacking MTSS1 and treated with the compound. In other words, the compound was able to help the ataxia in these mice. This was an exciting result indeed!

The researchers could have stopped there, but their curiosity pushed them to look at this pathway in other cerebellar ataxias. Low and behold, they observed the pathway that MTSS1 regulates, was in overdrive in SCA1, SCA2 and SCA5. These observations lead them to hypothesize that turning this pathway up was preventing neurons from communicating effectively with one another. They then treated the cerebellum from mouse models of SCA1, SCA2 and SCA5 with the compound that rescued motor movement in the mice lacking MTSS1. They found that they could use this drug to normalize the pathway and enable the neurons in the cerebellum to send proper signals again. This part of the study suggests that although numerous different genes involved in various different aspects of neuronal function cause SCAs, there exists common nodes between them. Identifying commonalities between diseases is a challenging and worthwhile pursuit.

This study was the first to use a mouse model to demonstrate how loss of MTSS1 causes cerebellar ataxia and deepened our understanding of its importance in maintaining effective communication between neurons. MTSS1 was shown to be a key regulator of a pathway shown to be vital for neuronal health and signaling between neurons. They demonstrated that this pathway is altered not only in mice lacking MTSS1, but also in SCA1, SCA2 and SCA5 mouse models. They demonstrated that by dialing this pathway back to normal using a drug, they could rescue the neuronal communication deficit that these diseases share and prolong the life of neurons in the cerebellum. This study lends hope to the possibility of a single treatment for numerous SCAs that would alleviate motor symptoms.

Note: The compound used in this study (dasatinib) is FDA approved for treatment of certain cancers. SCAsource would like to point out that, while this compound is clinically available, it would first need to be rigorously tested in clinical trials before approved for treatment of persons affected by SCA.

Key Terms

Ataxia: A loss of muscular control, leading to abnormal walking, speech changes and irregular eye movements.

Gene: A unit of heredity made up of DNA that fully or partially controls the development of specific traits

Mouse Model: A type of animal model with specific characteristics that allow for the study of various aspects of a human disease/condition.

MTSS1: Known as “Missing-in-metastasis” and “Metastasis suppressor protein 1”, MTSS1 is a protein involved in tumor metastasis, or when a tumor grows in a secondary location away from an initial cancer tumor. It also acts helps regulate Src kinase activity.

Neuron: a specialized cell type of the nervous system whose role is to transmit electrical signals.

Conflict of Interest Statement

Dr. Carolyn J. Adamski is a postdoctoral researcher at the Baylor College of Medicine, and has no conflicts of interest with the studies referenced in this article.

Dr. Judit M Perez Ortiz is a postdoctoral fellow at the Alzheimer’s Disease Center, University of Kansas Medical Center, and has no conflict of interest with the studies referenced in this article.

Citation of Article Reviewed

Brown A.S., et al. MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias. Proceedings of the National Academy of Sciences. 2018, DOI: 10.1073/pnas.1816177115, PMID: 30530649