Gene linked to development of the disease in those with a family history

Researchers at Rhode Island Hospital and The Warren Alpert Medical School of Brown University have discovered a gene that could hold the key to developing new treatments for Parkinson’s disease - a progressive and often debilitating movement disorder that affects as many as one million Americans.

According to the findings of the study, published online in the American Journal of Human Genetics, mutations in the gene, known as GIGYF2, appear to be directly linked to the development of Parkinson’s in people with a family history of the disease. The gene is one of only a handful linked to Parkinson’s and one of just two genes known to be a common contributor to this degenerative disease, which has no known cause or cure.

Although less than a quarter of all cases of Parkinson’s are familial, researchers believe genes like GIGYF2 can provide clues to the mechanisms behind Parkinson’s and could point to new treatments for the more common and sporadic forms of the disease.

“These findings may ultimately help open the door to the development of new therapeutic - and possibly even preventive - strategies that target the underlying cause of Parkinson’s disease, improving the quality of life of the many people worldwide who are affected by this devastating disorder,” said senior author Robert J. Smith, M.D., director of the division of endocrinology and the Hallett Center for Diabetes and Endocrinology at Rhode Island Hospital and professor of medicine at Alpert Medical School.

Their research also revealed an intriguing secondary finding — the possible association between Parkinson’s and insulin and the related hormone known as insulin-like growth factor (IGF). This joins a small but growing body of research linking insulin and IGF to Parkinson’s disease and other neurodegenerative disorders, such as Alzheimer’s.

“A better understanding of the link between insulin or IGF and Parkinson’s may lead us to new treatment strategies for Parkinson’s and also new insights into the connection between diabetes and nervous system disorders,” Smith said.

Parkinson’s is one of the most common neurodegenerative disorders, second only to Alzheimer’s, affecting between one and two percent of the population above age 60. The disease occurs when certain nerve cells in the part of the brain that controls muscle movement either die or become impaired. Normally, these cells produce a vital chemical known as dopamine, which allows smooth, coordinated function of the body’s muscles and movement. When the dopamine-producing cells are damaged, the symptoms of Parkinson’s appear - including tremors, slow movements, stiffness, and difficulty with balance or coordination.

Smith, an endocrinologist, and his team at Rhode Island Hospital and Brown typically focus on proteins important to the function of insulin and IGF. They initially identified GIGYF2 nearly five years ago because of its potential involvement in IGF and insulin signaling systems, but did not explore an association with Parkinson’s at that time.

In the current study, they examined where GIGYF2 is located on the human genome in hopes of learning more about the gene’s function, and discovered that it is right in the center of a chromosomal region linked to Parkinson’s. Specifically, it appears GIGYF2 resides on PARK11 - a region that was initially identified through a genetic analysis of families with Parkinson’s disease.

Because of the potential links between Parkinson’s, IGF and diabetes, Smith and his team decided to investigate the involvement of GIGYF2 in Parkinson’s. Colleagues in Milan, Italy and Paris, France provided close to 250 DNA samples from patients who had Parkinson’s and at least one first-degree relative (parent, child or sibling) with the disease. This included 123 Italian patients and 126 French patients. For comparison, they also studied DNA from more than 200 unrelated healthy controls from both countries.

Following gene sequencing and mutation analysis, the researchers identified seven different forms of GIGYF2 mutations occurring in 12 different people - approximately five percent of those in the study. Eight of these patients had at least one parent with Parkinson’s, one had both parents affected, and three had one sibling affected. When available, relatives with Parkinson’s were also sampled and the researchers found they carried the same mutation, which led to single amino acid substitutions in the protein encoded by the GIGYF2 gene. None of the mutations were observed in the healthy controls.

“Our data provides strong support for GIGYF2 as a PARK11 gene with a causal role in familial Parkinson’s disease,” said Smith. “The next step is to zero in on this gene to learn more about its involvement in triggering Parkinson’s. It will also be important to evaluate additional and larger families with Parkinson’s and these genetic mutations, as well as the frequency of GIGYF2 mutations in patients with the more common, idiopathic form of the disease.”

Thanks for this, Madelyn. I think that these familial PD genes will eventually provide the key to unlocking the mysteries of Parkinson's; the sooner the better, for the sake of my children and grandchildren!

Robert

are they not learning to 'modulate' the bad genes ? can some body explain what they are trying to do in simpler language?

the Rhode Island scientist studying the gene in Madelyn's post.

The significance of these discoveries of gene mutations found to be associated with Parkinson's goes something like this;
Each gene so discovered reveals another protein involved in metabolic and/or developmental pathways essential to maintaining normal brain function. The presence of mutations in such a protein, especially if it has a known activity, identifies its activity as being involved in the pathway(s) of normal function. By studying where that protein is present, and how the discovered mutation(s) affect its activity, important clues as to how one might correct the malfunction may be revealed.
Ten or twelve such PD-related genes have thus far been discovered in the last ten or fifteen years. Unfortunately,the true function of only one or two of the proteins produced by those genes are known. The identification of each such protein and the eventual discovery of their functions provides more pieces of the puzzle that should reveal the big picture of normal brain function and how to restore it.

Robert

to know what you can do once you have identified the mutated genes responsible fo PD even if we are a long way from that point.

the ultimate medical object of identifying PD-related genes and their functions in your initial response. That is, to "modulate their activity". Keep in mind that the great majority of cases of PD are not familial or genetically transmitted. Most are so-called "idiopathic" or "sporadic" cases.

To take a couple of examples of types found to be familial;
Alpha synucein was one of the first PD-related genes identified about twelve years ago. It was also found to be a major constituent of Lewey bodies, the microscopic protein aggregates present in the substantia nigra of Parkinson's patients, and which, along with the loss of dopamine-producing neurons in that region, constitutes the only true diagnostic test for the disease. This post-mortem finding is present in both sporadic or familial cases.
Two "point mutations" (single amino acid changes) discovered in synuclein increase the tendency of the affected proteins to form toxic aggregates which eventually form Lewey bodies. Other pateints who do not have alpha synuclein point mutatuons have duplicates or even triplicates of the alpha synuclein gene, causing them to produce an excess of the protein. Still others have genetic alterations which also result in the production of excess synuclein of normal structure without duplication of the gene. This appears to be a result of alterations in so-called "control" gene elements responsible for governing the rate of synthesis of alpha synuclein. So it seems that PD can result from both "crippled" mutant alpha synuclein and an excessive production of the structurally normal protein.
Since there are no known diseases associated with decreased production of alpha synuclein, and mice in which the gene has been experimentally inactivated are healthy, a promising approach to treating either familial or sporadic Parkinson's would be to find a drug that specifically decreases the procuction of alpha synuclein, thus avoiding or delaying its neurotoxic aggregation.

Another more common cause of PD, found most often in familial cases, but occasionally in sporadic ones, is point mutations in the gene for a protein referred to as LRRK2. This protein appears to be an enzyme of the "kinase" family, thus the K in its name. This very large family of enzymes (there are hundreds of different kinases) catalyze the addition of the phosphate group to different molecules. The two most commonly found single-point mutant forms of LRRK2 present in familial PD cases were discovered to have higher enzyme activity than the normal, non-mutant protein. Therefore it would seem that a kinase inhibitor drug specific for this molecule would be a logical approach to this particular form of PD.

My apologies to those who made it this far, but did so with glazed eyes.

Robert

Although I am not sure I know the meaning of "pritty well nailed" but thank you for your excellent explanation .. I made it to the end and I have a better idea now..
We are so lucky to have you on the forum .. and .. I say it not because I am trying to be nice but because it is true