Polyglutamine (polyQ) is a portion of a protein that contains a long segment of glutamine amino acids, normally ranging from 10 to 40 glutamine residues. When the polyglutamine tract, sometimes called the polyglutamine tail, is abnormally long, it can lead to neurodegenerative disease in some individuals. Some of the major diseases that result from this abnormality include Huntington Disease, Kennedy Disease, Haw River Syndrome, and various spinocerebellar ataxias.
The formation of an unusually long polyglutamine tract is often caused by genetic mutations. Many of these mutations are inherited; Kennedy Disease, for example, is X-linked recessive, meaning that the disease gene mutation is located on the X-chromosome and that an individual must possess two copies of the gene in order to develop the disease. The other common neurodegenerative diseases caused by increased polyQ tract length are autosomal dominant, which means that the gene is present on a non-sex chromosome and that the individual only needs one copy of the gene to develop the disease.
Genetic mutations often include excess repeats of the three-nucleotide sequence of cytidine-adenosine-guanosine (CAG). These triplets, known as CAG repeats, each code for the addition of one glutamine residue to the polyglutamine tail. When there are too many repeats the tail becomes too long, creating problems for the protein molecule and ultimately for the body as a whole. The number of additional CAG repeats varies for each disease, and some individuals with a high number of CAG repeats don’t end up developing any form of neurodegenerative disease, indicating that there is some degree of chance or environmental factors that contribute to disease development.
Long polyQ tails can create a couple of main problems within the body. First, they can interfere with the function or shape of the proteins to which they are attached. Extra glutamine residues can often cause a protein to misfold, hindering its ability to function normally within a cell. Additionally, abnormal polyglutamine tails can prevent these malfunctioning proteins from being fixed or destroyed by the cell’s internal defense mechanisms, worsening their harmful effects.
Second, even when the cell’s enzymes are able to correct the proteins by snipping off the excess polyglutamine units, the units can often aggregate in protein tangles. Not only can these tangles get in the way of normal cell processes, but they can also inadvertently trap other proteins and molecules, further damaging the cell. Each of the different neurodegenerative diseases arises from a slightly different mechanism, but all include some level of abnormal polyglutamine tail length that damages the nerve cells.