Written by Carrie A. Sheeler Edited by Dr. Ronald A.M. Buijsen
RNAi reduces levels of disease-causing Ataxin-1 in SCA1 model mice, easing symptoms of disease when injected both before and after symptom onset.
Lowering the amount of the disease-causing mutant Ataxin-1 protein in affected cells and tissues improves symptoms of disease in spinocerebellar ataxia type 1 (SCA1) mouse models. Like patients with SCA1, mouse models exhibit worsening coordination and degeneration of neurons, beginning in adulthood. Previous work has used genetic manipulation before disease onset (Zu et al 2004). This prevents or delays the onset of disease in SCA1 mouse models. When this is done soon after the onset of symptoms, associated markers of disease are reversed. This suggests that there is a window of time after symptoms start wherein mutant Ataxin-1 can be targeted to improve patient outlook. The 2016 paper by Keiser and colleagues seeks to further study this effect, using RNA interference as a strategy to reduce disease-causing levels of Ataxin-1. As there is no current treatment for Ataxin-1, this is an important step towards assessing possible treatment strategies that could be useful in patients.
Current strategies seek to decrease the amount of Ataxin-1 made in cells by targeting messenger RNA (mRNA)- the blueprints for proteins in a cell- for destruction. RNA interference (RNAi) is one such method which harnesses normal cellular processes to degrade specific mRNAs. In Keiser’s 2016 paper, a modified virus carrying a short sequence of DNA is injected into the brain of a mouse with SCA1. When this virus is injected, the DNA sequence enters the cells of nearby brain regions and stops the production of specific mRNA. In this case, it is Ataxin-1 mRNA that is specifically targeted. As Ataxin-1 mRNA are destroyed, the amount of Ataxin-1 protein made in the cell decreases.