Most people with a rare type of dementia called primary progressive aphasia (PPA) have a specific combination of prion gene variants, a new study shows.
The study is the first to link the prion protein gene to this disorder. It was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the December 2005 issue of the Annals of Neurology.
The researchers, led by James A. Mastrianni, M.D., Ph.D., of the University of Chicago, also looked at the prion protein gene in people with Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) and did not find any association with specific gene variants in those disorders.
PPA is classified as a type of frontotemporal dementia because of the pattern of brain degeneration it causes. The primary symptoms of the disease are problems speaking or understanding speech, and these problems gradually get worse over time. People with PPA also may develop difficulty with math. Most other functions remain normal for at least two years after the language symptoms appear, but the disease may eventually cause other changes, such as problems with memory, reasoning, and spatial abilities. While PPA sometimes runs in families, it has never before been linked to variations in a specific gene.
Unlike the abnormal disease-causing prions linked to Creutzfeldt-Jakob disease (CJD) and other so-called "prion diseases", the normal prion protein is found in everyone. The gene that codes for the normal protein has several common variants. One variant of the gene codes for an amino acid called methionine at a point called codon 129, while another version codes for the amino acid valine at codon 129. These variants appear to influence disease susceptibility and symptoms in CJD and other prion diseases, probably because they determine how the prion protein folds. Proteins' folded shapes affect how well they can function. Some protein shapes also interfere with normal cellular processes.
People normally have two copies of every gene. In the new study, Dr. Mastrianni and his colleagues found that almost 85 percent of the people with PPA who took part in this study had one copy of the prion gene coding for the methionine variant and the other coding for valine. "The association between this gene combination and the disease is really dramatic," he says. However, not all people with the two gene variants develop PPA. Therefore the prion gene is probably not the primary cause of the disease, he adds.
The researchers think that the methionine/valine combination leaves people susceptible to PPA in ways that are not yet understood. Previous studies have suggested that normal prion proteins carry out a variety of functions, from cellular delivery of copper to cell signaling and even triggering or preventing cell death. The proteins may work either better or worse depending on which gene variants people inherit. Any of the proteins' normal activities could be important in the chain of events that leads to PPA.
"This is a new case where prion genes are linked to a neurological disorder, and it suggests that we need to learn more about the normal function of prions in the nervous system in order to better understand their role in disease," says Michael Nunn, Ph.D., the NIH neurology institute's program director for this study.
The findings conflict with previous studies that found an association between Alzheimer's disease and a specific variant of the prion protein. However, the protein could still play a role in that disease. "We aren't saying there is no link to Alzheimer's disease – just that there isn't any association with the genetic state of the prion protein gene in our patient sample," explains Dr. Mastrianni.
PPA does not appear to be a prion disease in the traditional sense, Dr. Mastrianni adds. He doubts that the disease is transmissible in the way that CJD is, although he and his colleagues are carrying out studies using transgenic mice in order to test that possibility.
The investigators are also planning studies to examine how the prion variations may influence development of PPA. The studies may help researchers understand other neurodegenerative diseases as well, Dr. Mastrianni says.
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