RNA-binding Protein Found to Play a Role in SCA2 Neurodegeneration

Written by Dr. Hayley McLoughlin Edited by Dr. Gülin Öz

Is Staufen1 a kink in the SCA2 toxicity chain that can be exploited?

When a cell is stressed, it can initiate a mechanism to protect messenger RNAs (mRNAs) from harmful conditions. It does this by segregating the mRNAs, then packaging them up in droplets known as RNA stress granules. ATXN2, the protein that is mutated in SCA2, has previously been reported as a key component in the formation of these RNA stress granules (Nonhoff et al., 2007). This observation has led researchers to take a closer look at stress granule components, especially in the context of SCA2 disease tissues.

Image of a metal chain. If a “weak link” is found in the chain of events that go amiss in SCA2, scientists could focus on this area to research possible treatment. Photo by Pixabay on Pexels.com

In addition to ATXN2, there are many other proteins that are associated with stress granules. Over a decade ago, the RNA binding protein, Staufen1 (STAU1) was described as one such protein (Thomas et al., 2005). STAU1 functions in a cell as the RNA garbage truck, selectively binding to specific regions in mRNA and sending them out of stress granules to be degraded.

In a recent Nature Communications report, Dr. Stefan Pulst’s research group explored the relationship between ATXN2 and STAU1. They found that ATXN2 and STAU1 proteins, under conditions of stress, are found in close proximity to one another in both human SCA2 cells and an SCA2 mouse model. Moreover, they found a significant increase in STAU1 levels in both the SCA2 cell lines and the SCA2 mouse tissue relative to healthy controls. Since STAU1 facilitates RNA decay, the researchers then sought to determine whether these increased levels of STAU1 affected the amount of mRNA in SCA2 cells. They found that this overabundance of STAU1 decimated the levels of many important mRNA molecules, likely contributing to a toxic cascade of abnormal cellular function. One of these important mRNAs is used by cells to make PCP2, a protein that has been well-studied in the field of SCA2 research. In previous studies, it has been observed that some vulnerable cell populations show a progressive reduction of PCP2 levels in SCA2. Here, the authors show that they can recover the levels of PCP2 in SCA2 mice after treating the mice with a gene therapy that reduces STAU1 levels in the brain.

The most exciting data from this report are the pathological and behavioral results of this STAU1 reduction. When they reduced STAU1 levels by 50% in their SCA2 mouse model, the authors found that the pathological and behavioral effects of the disease were diminished. While this is a remarkable finding, it is important to note that further animal studies of STAU1 must be performed before these results can be taken to the clinic. Future experiments will likely involve other gene silencing technologies – possibly even small molecules designed to target the interaction of STAU1 with specific RNA targets.

The results of this study also reach beyond the world of SCAs. Recent research has revealed a strong link between stress granule formation and other neurodegenerative diseases, such as ALS (also known as “Lou Gehrig’s disease”) and Fragile X syndrome (the most common identified cause of autism). Future investigations of STAU1 dysregulation could greatly improve our understanding of these disorders. In the field of SCA2 research, though, the authors acknowledge that there is still much to be learned about the exact reason STAU1 levels are elevated during disease. Further studies of this mechanism may lead to additional targetable break points in the SCA2 toxicity chain.

Key Terms

Messenger RNA (mRNAs): the RNA molecules that ‘translate’ the genetic code from DNA so that proteins can be built based on that code.

Stress granules: membrane-less globules in a cell that contain/protect messenger RNAs from harmful cellular stress conditions.

Staufen1 (STAU1): a protein that binds to specific messenger RNAs and delivers them to protein machinery for degradation.

PCP2: a protein that is produced at high levels in cerebellar Purkinje cells, which are progressively lost throughout the course of SCA2 disease.

Conflict of Interest Statement

The author and editor declare no conflicts of interests.

Citation of Article Reviewed

Paul, S., et al., Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration. Nat Commun, 2018. 9(1): p. 3648. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128856/)

References

Nonhoff, U., et al., Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell, 2007. 18(4): p. 1385-96.
Thomas, M.G., et al., Staufen recruitment into stress granules does not affect early mRNA transport in oligodendrocytes. Mol Biol Cell, 2005. 16(1): p. 405-20.