SCA36 is caused by mutations in the NOP56 gene. The NOP56 gene provides instructions for making a protein called nucleolar protein 56, which is primarily found in the nucleus of nerve cells (), particularly those in the cerebellum. This protein is one part (subunit) of the ribonucleoprotein complex, which is composed of proteins and molecules of RNA, DNA’s chemical cousin. The ribonucleoprotein complex is needed to make cellular structures called , which process the cell’s genetic instructions to create proteins.
The NOP56 gene mutations that cause SCA36 involve a string of six DNA building blocks (nucleotides) located in an area of the gene known as intron 1. This string of six nucleotides (known as a hexanucleotide) is represented by the letters GGCCTG and normally appears multiple times in a row. In healthy individuals, GGCCTG is repeated 3 to 14 times within the gene. In people with SCA36, GGCCTG is repeated at least 650 times. It is unclear if 15 to 649 repeats of this hexanucleotide cause any signs or symptoms.
To make proteins from the genetic instructions carried in genes, a molecule called (mRNA) is formed. This molecule acts as a genetic blueprint for protein production. However, a large increase in the number of GGCCTG repeats in the NOP56 gene disrupts the normal structure of NOP56 mRNA. Abnormal NOP56 mRNA molecules form clumps called RNA foci within of neurons. Other proteins become trapped in the RNA foci, where they cannot function. These proteins may be important for controlling gene activity or protein production.
Additionally, researchers believe that the large expansion of the hexanucleotide repeat in the NOP56 gene may reduce the activity of a nearby gene called MIR1292. The MIR1292 gene provides instructions for making a type of RNA that regulates the activity (expression) of genes that produce proteins called glutamate receptors. These proteins are found on the surface of neurons and allow these cells to communicate with one another. A decrease in the production of Mir1292 RNA can lead to an increase in the production of glutamate receptors. The increased receptor activity may overexcite neurons, which disrupts normal communication between cells and can contribute to ataxia.
The combination of RNA foci and overly excited neurons likely leads to the death of these cells over time. Because the NOP56 gene is especially active in neurons in , these cells are particularly affected by expansion of the gene, leading to cerebellar atrophy. Deterioration in this part of the brain leads to ataxia and the other signs and symptoms of SCA36.