Written by Stephanie Coffin Edited by Dr. Brenda Toscano
Ataxin-1 may not be the only protein important in driving neurodegeneration in SCA1
Why does a protein that cause disease only cause toxicity in specific regions of the brain, despite being in all cells of the body? This is the question authors attempt to answer in this article, with a focus on spinocerebellar ataxia type 1 (SCA1) and the disease causing protein, Ataxin-1. SCA1 is a polyglutamine expansion disorder, meaning patients with the disease have a CAG repeat in the ATXN1 gene that is larger than that of the healthy population. This mutant allele is then translated into a mutant protein, causing SCA1. Ataxin-1 protein is expressed throughout the entire brain, however, toxicity (cell death and problems) is mainly restricted to neurons of the cerebellum and brainstem. This phenomenon is called “selective vulnerability” and refers to disorders in which a restricted group of neurons degenerate, despite widespread expression of the disease protein. Selective vulnerability occurs in many diseases, including Alzheimer’s, Huntington’s, and Parkinson’s disease and is currently under investigation by many scientists in the field of neurodegeneration.
In SCA1, this selective vulnerability can be narrowed further in the cerebellum. The cerebellum is broken down into lobules (I-X), with lobules II-V described as the anterior region and lobules IX-X as the nodular zone. Studies have previously shown cerebellar Purkinje cells to be particularly sensitive to mutant ataxin-1, and within the cerebellum, neurons in the anterior region degenerate faster than those in the nodular zone. This paper wanted to understand the mechanism of this interesting biology, hypothesizing that there are genes whose are expressed mainly in these zones could correlate with the pattern of Purkinje cell degeneration. To this end, the authors used the mouse model ataxin-1 [82Q], which overexpresses human ataxin-1 with 82 CAG repeats specifically in cerebellar Purkinje cells.
First, the authors confirmed the finding that neurons from the anterior region of the cerebellum degenerate earlier than those in the nodular zone. They did this by assessing the health and number of Purkinje cells, which indeed appeared to be better in the cells located in the nodular zone. Next, techniques assessing expression of RNA in SCA1 and control cerebellum, showed that there are a number of genes which are uniquely dysregulated in the anterior cerebellum of SCA1 mice. Neurons function and communicate with each other via ion channels, and interestingly, the genes found to be dysregulated in the anterior cerebellum of SCA1 mice were related to ion channel signaling.Continue reading “Levels of Capicua may make SCA1 neurodegeneration worse in parts of the brain”