An abnormally long polyglutamine tract in proteins can cause neurodegenerative diseases such as Huntington’s and Kennedy’s disease. Genetic mutations, including excess CAG repeats, can cause the abnormality, which can interfere with protein function and cause tangles of protein that damage nerve cells.
Polyglutamine (polyQ) is a portion of a protein that contains a long segment of the amino acid glutamine, usually between 10 and 40 glutamine residues. When the polyglutamine tract, sometimes called the polyglutamine tail, is abnormally long, it can lead to neurodegenerative diseases in some individuals. Some of the major diseases that result from this anomaly include Huntington’s disease, Kennedy’s disease, Haw River syndrome, and various spinocerebellar ataxias.
The formation of an unusually long polyglutamic tract is often caused by genetic mutations. Many of these mutations are inherited; Kennedy disease, for example, is X-linked recessive, which means that the disease gene mutation is located on the X chromosome, and an individual must have two copies of the gene to develop the disease. The other common neurodegenerative diseases caused by increased polyQ tract length are autosomal dominant, meaning that the gene is present on a non-sex chromosome and the individual only needs one copy of the gene to develop the disease.
Genetic mutations often include excess repeats of the cytidine-adenosine-guanosine (CAG) three-nucleotide sequence. These triplets, known as CAG repeats, each code for the addition of a glutamine residue to the polyglutamine tail. When there are too many repetitions the queue 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 large numbers of CAG repeats do not end up developing any form of neurodegenerative disease, indicating that there is some degree of chance or environmental factors contributing to the development of the disease.
Long polyQ tails can create a couple of major problems within the body. First, they can interfere with the function or shape of the proteins they are attached to. Extra glutamine residues can often cause a protein to misfold, hampering its ability to function normally within a cell. Furthermore, 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 fix proteins by cutting away excess polyglutamine units, the units can often clump together into tangles of protein. Not only can these tangles get in the way of normal cellular processes, they can also inadvertently entangle other proteins and molecules, further damaging the cell. Each of the different neurodegenerative diseases results from a slightly different mechanism, but they all include some level of abnormal polyglutamine tail length that damages nerve cells.
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