Written by Dr. Terri M Driessen Edited by Dr. W.M.C. van Roon-Mom
Antisense oligonucleotides: a potential treatment for SCA3 that partially rescues SCA3 disease mouse models
Identifying new ways to slow down or delay neurodegenerative diseases has been a key research focus in the SCA field. There are many avenues that scientists can take to address this question. One method is to target the disease-causing protein: by lowering the levels of the disease-causing protein, scientists may be able to alter disease progression. These methods have recently been used in studies in other neurodegenerative disorders, like SCA2, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease.
Prior work by the laboratory of Hank Paulson at the University of Michigan has suggested these methods may also work in SCA3. They used antisense oligonucleotides (ASOs) to lower the SCA3 disease-causing protein. ASOs are short DNA sequences that bind to specific pieces of RNA. When the ASOs bind to RNA, it is broken down and no protein is made. The Paulson laboratory designed ASOs that bind to ATXN3, which is the RNA associated with SCA3. These ASOs were able to lower the expression of mutant ATXN3 (Moore, et al. 2017). Importantly, they were capable of lowering the expression of mutant ATXN3 in both mouse models of SCA3 and SCA3 patient fibroblasts (Moore, et al. 2017). By removing the SCA3-causing protein from cells, they predicted that the cells would have a better chance at surviving.
This previous work was promising, but several questions remained. How long would one ASO treatment work? Would the ASO work even after the SCA3 mice started showing symptoms? Are there any obvious side effects, like increased inflammation, after ASO injection? And importantly, would lowering ATXN3 levels help with motor coordination problems in SCA3 mice?
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.
Written by Dr. Chandrakanth Edamakanti Edited by Dr. Hayley McLoughlin
Recent study decodes the protein signature of toxic Purkinje cells, finding that Purkinje cell mTORC1 signaling is impaired in SCA1.
Spinocerebellar ataxia type 1 (SCA1) is a late onset cerebellar neurodegenerative disorder caused by a mutation (in this case, an abnormal polyglutamine stretch) in the Ataxin-1 gene. People with this condition experience problems with coordination and balance, a set of symptoms known as ataxia. The protein produced by this faulty gene, ATXN1, is particularly toxic to the Purkinje cells, the sole output neurons of the cerebellum. However, the reason behind the selective toxicity of Purkinje cells in SCA1 is unknown.
The main focus of this article is to address this question. It is the first study to find the protein signature of toxic Purkinje cells in SCA1 mice. In the end, the authors identified widespread protein changes that are associated with Purkinje cell toxicity.
Written by Logan Morrison Edited by Dr. Sriram Jayabal
Stanford researchers accidentally discover a new role (reward prediction) for the cerebellum, the primary brain region affected by spinocerebellar ataxias.
Would you believe that the part of your brain that enables you to perform simple, everyday tasks (like jogging or walking) also controls your ability to do more complex tasks (like throwing a curve ball) with accuracy? It’s true! Every one of our body’s movements is adjusted by a brain region known as the cerebellum – a primary area of pathology in spinocerebellar ataxias. The name “cerebellum” is a combination of the Latin word for the brain – cerebrum – and the Latin suffix -ellus, which means small. While this “little brain” might not take up much room, it actually contains the vast majority of the nerve cells (known as neurons) in the central nervous system1. Take a look at the image included with this article to see for yourself: even without the red highlighting, the cerebellum should be instantly recognizable as the distinctive structure in the bottom right, so folded and densely-packed that it looks a bit like something you’d find on the branches of a fern or shrub. Among these many folds are the circuits that fine-tune our motor output, providing us with the ability to move our bodies with ease and precision.
For decades, not much else was said about the function of the cerebellum beyond its primary role in tweaking movement. Recently, though, there have been some hints that there is more to this part of the brain than we might have thought: brain imaging studies of patients suffering from bipolar disorder, for instance, have sometimes shown abnormalities in the cerebellum3, 4. Cerebellar abnormalities have been implicated in a variety of other diseases, as well, including autism spectrum disorders, schizophrenia, Alzheimer’s disease, and multiple sclerosis5, 6. Now, thanks to the hard work of scientists at Stanford University7 – as well as a bit of luck – we know that the cerebellum is not only involved in how we move, but why.