Written by Dr. Judit M Perez Ortiz Edited by Dr. Maria do Carmo Costa
A druggable target in Spinocerebellar Ataxia type 1 (SCA1) shows promise in treating cerebellar and non-cerebellar aspects of disease.
Spinocerebellar Ataxia type 1 (SCA1) is a neurodegenerative disease that typically starts with coordination difficulties (ataxia) in mid- to late-adulthood, worsens over time, and shortens life expectancy. SCA1 runs in families, as it is caused by a genetic mutation in a gene called Ataxin-1. The gene’s instructions make a protein conveniently also termed “ataxin-1”. Healthy ataxin-1 is important in orchestrating important processes in brain cells.
In SCA1, mutant ataxin-1 drives disease by affecting these important cellular processes. In patients with SCA1, their ataxin-1 protein has a polyglutamine repeat expansion mutation that makes the protein behave in toxic ways. The disarray caused by mutant ataxin-1 protein slowly deteriorates and ultimately compromises the health of the brain areas involved. Research on this topic is very rich and increasingly exciting. SCA1 treatments under investigation explore different strategies to minimize the insult caused by mutant ataxin-1.
New work by Nitschke and colleagues takes previous efforts a step further towards this goal by delving deeper into the promises and limitations of an exciting therapeutic “angle” in the ataxin-1 protein itself.
A Flippable Switch
Currently, there are no approved therapies for SCA1. The ataxia scientific community has identified a few possible approaches. One approach is to improve the consequence of disease (brain cell miscommunication, brain cell survival). Another approach is to address the crux of the problem (disease-causing mutant ataxin-1 protein). The disease-causing abnormality in SCA1 is a polyglutamine expansion. This mutation causes ataxin-1 to malfunction and this damages certain brain cells. To make matters worse, the polyglutamine mutation makes the mutant ataxin-1 stick around longer than it should. How can we help cells get rid of mutant ataxin-1?
At the tail-end of the protein, there a site called Serine 776. It is a very attractive treatment target because it acts like a “switch” that influences the disease-causing potential of mutant ataxin-1 protein in cells! How does this happen?
Serine is the seven hundred and seventy sixth amino acid in the ataxin-1 protein sequence. When Serine 776 is phosphorylated, this causes a sort of “switch” in ataxin-1’s to-do lists in the cell. In the case of healthy ataxin-1, this helps fine tune its function in favorable ways. For example, a brain cell may need ataxin-1 to stick around a little longer to keep working. The cells keeps ataxin-1 around by phosphorylating the Serine 776 switch. Or, a brain cell may also need ataxin-1 protein to focus on “talking” to certain proteins which it does by phosphorylating Serine 776.
In the case of mutant ataxin-1, Serine 776 is unwanted as this “switch” makes the bad ataxin-1 stick around too long and “talk” to the wrong proteins. It makes sense then, that preventing the undesirable phosphorylation of mutant polyglutamine ataxin-1 could be an approach to mitigate its damage. In fact, we know that in mice genetically engineered to make mutant human ataxin-1 exclusively in their cerebellum, interfering with Serine 776 phosphorylation helps with the ataxia difficulties!
One of the promising aspects of targeting Serine 776 phosphorylation is that there already are drugs designed to interrupt phosphorylation of other proteins in other diseases. The quest for therapies addressing this aspect of disease has yielded a small number of promising druggable candidates in animal models. The hope is that we may develop a drug that reduces phosphorylation of Serine 776 in mutant ataxin-1 to treat disease in human patients with SCA1.
Beyond Cerebellar Ataxia
SCA1 is not a static disease and it is not exclusive to the cerebellum. For reasons that are not entirely understood, mutant ataxin-1 damages different areas of the brain and this evolves over time. Patients with SCA1 initially have difficulties with balance and coordination (ataxia) as a result of degeneration of the cerebellum. As the years go on and the disease progresses, patients notice troubles with memory as a result of disease in the hippocampus. Finally, as disease continues, patients have trouble coordinating the function of breathing and swallowing as a result of brainstem damage. This last phase places individuals with SCA1 in a more vulnerable state and poses a risk to life. SCA1 is a disease that initially affects quality of life with coordination difficulties but can eventually shorten it as well.
So, targeting Serine 776 helps ataxia, but can it be a life-saving druggable candidate for the treatment of SCA1?
To answer this question, the investigators genetically engineered two mouse models. The first mouse expresses mutant ataxin-1 with Serine 776 that can be phosphorylated (S776). The second mouse model has mutant ataxin-1 with Serine 776 that cannot be phosphorylated (S776A). This approach had been previously done just in the Purkinje neurons in the cerebellum. This time the scientists applied the same approach to all cells in the body. They did this to ask the question of what is the importance of Serine 776 beyond the cerebellum.
The investigators found that just as was previously seen in the cerebellum, mutant ataxin-1 protein in the S776A configuration is also less abundant than in the S776 form in hippocampus, brain stem, and other non-cerebellar tissues. This is the first study to show that phosphorylation of Serine 776 is important for controlling durability of ataxin-1 protein (and its potential for causing toxic effects) in cells outside the cerebellum.
Does interfering with Serine 776 phosphorylation treat non-ataxia symptoms?
To understand the significance of these findings, the investigators put the mice to the test. As a result of the disease-causing protein, mice with mutant S776 ataxin-1 have many features that affect SCA1 patients, including respiratory dysfunction, weakness, memory issues, failure to gain normal weight, and shortened lifespan. These are important aspects of disease that impact SCA1 patients’ quality of life.
The study revealed an exciting and hopeful finding: S776A mice showed improved muscle strength, respiratory function, and prolonged lifespan compared to S776 mice! Unfortunately, the S776A modification did not help with the memory or low weight issues. This work is the first study to demonstrate, in mouse models, that Serine 776 is a druggable target to treat the more sinister symptoms of SCA1 beyond ataxia. The study was also humbling in that it taught us that we may need another target for the memory deficits and healthy weight regulation to support important aspects of health in SCA1.
Narrowing down your target
What about the healthy ataxin-1 protein? Until the work described by Nitschke and colleagues, we didn’t know what would happen if the healthy ataxin-1 protein was also not phosphorylated. To understand this, it should be mentioned that in patients with SCA1, the disease-causing mutant ataxin-1 (with an expanded polyglutamine repeat) and healthy normal ataxin-1 (with a normal polyglutamine repeat length) coexist. In people without SCA1, our cells just have healthy ataxin-1.
While this and previous work showed that interrupting phosphorylation of Serine 776 has beneficial effects in cells with mutant ataxin-1, we did not know what happens to cells that live with normal ataxin-1 as well. It turns out that manipulating the Serine 776 phosphorylation switch in the healthy ataxin-1 protein gets in the way of the therapeutic effect when the same manipulation is done with the mutant protein around. The study showed that mice S776A in normal ataxin-1 as well as mutant ataxin-1 had lesser clinical benefit than those with S776A in mutant Aaaxin-1 alone.
A sobering insight
Previous work in mouse models of SCA1 had taught us that interrupting Serine 776 phosphorylation “switch” in the mutant form of the ataxin-1 protein could treat their ataxia. This study extends our appreciation of this therapeutic opportunity in two major ways. First, it validates Serine 776 as a therapeutic target for non-cerebellar, lethal aspects of disease. Second, it recognizes that to achieve therapeutic efficacy, therapy needs to be tailored to block phosphorylation of the mutant protein, while leaving the healthy ataxin-1 protein undisturbed. This work is another important contribution to fine-tuning therapy options and their safety for patients and families affected by SCA1.
Polyglutamine Expansion Disease: A family of diseases caused by an expansion of glutamine amino acids in certain proteins. You can learn more about polyglutamine expansion in this Snapshot.
Mouse Model: A type of animal model with specific characteristics that allow for the study of various aspects of a human disease/condition. You can learn about mouse models in this Snapshot.
Conflict of Interest Statement
The author and editor declare no conflict of interest.
Citation of Article Reviewed
Nitschke L, Coffin SL, Xhako E, El-Najjar DB, Orengo JP, Alcala E, Dai Y, Wan YW, Liu Z, Orr HT, Zoghbi HY. Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1. JCI Insight. 2021 Feb 8;6(3):e144955. https://pubmed.ncbi.nlm.nih.gov/33554954/