Written by Carrie A. Sheeler Edited by Dr. Marija Cvetanovic
Group 1 p21-associated kinases (PAKs) present a new avenue for SCA1 research.
Spinocerebellar ataxia type 1 (SCA1) is caused by a specific mutation in the Ataxin1 gene, which causes the protein that’s made from that gene (also called Ataxin1) to have an abnormally elongated polyglutamine (polyQ) tract. This leads to dysfunction and death in the affected cells of the brain (predominantly Purkinje neurons in the cerebellum), which causes symptoms in patients that include a progressive worsening of coordination and balance. While there is currently no cure for SCA1, several studies suggest that lowering the amount of Ataxin1 protein in the brain may delay the onset of the disease and decrease the severity of symptoms. This leads us to an important question: how do we most effectively decrease the amount of Ataxin1 in SCA1 patients? One paper recently published by Bondar and colleagues suggests that a multi-pronged approach could be the most effective means of reducing this toxic protein.
The amount of any specific protein in the body can be altered by either decreasing the amount of protein produced or increasing the rate at which cells break those proteins down. Proteins are made using messenger RNA (mRNA), which is created following specific instructions found in DNA. Decreasing the production or stability of mRNA decreases the amount of corresponding protein made. One way to target the mRNA that causes production of a specific protein is with antisense oligonucleotides (ASOs). ASOs are designed to target specific mRNA sequences by binding to them directly. Binding of ASOs to mRNA causes those molecules to be marked for destruction within the cell. Proteins in the body are also regularly recycled, but without the blueprints to build a new protein, cells cannot replenish the protein supply it loses over time. So, if Ataxin1 mRNAs are targeted and destroyed by ASO treatment, the amount of Ataxin1 in our cells would theoretically decrease.
Some proteins can also be altered by other proteins, creating another way that their stability, shape, and function can be regulated. This leads us to the other way we can alter the amount of a specific protein in a cell: regulating the regulators. In terms of SCA1, this could mean removing a protein that helps stabilize Ataxin1 or increasing the production of a protein that breaks Ataxin1 down. Previous research has identified several proteins of interest that regulate Ataxin1 protein stability, including several kinases. Kinases are a class of proteins that transfer a phosphate group from adenosine triphosphate (ATP) to another protein in the cell. The addition of this phosphate group acts as an energy source to the receiving protein, altering its stability or how it interacts with other molecules in the cell (usually by causing it to change its shape). Recently, Bondar and colleagues have identified a new potential regulator of Ataxin1: a group of proteins known as p21-activated kinases (PAKs) (Bondar et al 2018).