What Can Alzheimer’s Tell us About Parkinson’s?

From James Beck, Ph.D., Director of Research Programs

Understanding how Parkinson’s disease starts and how it progresses remain two of the key unanswered questions about the disease. This is why a recent story in the New York Times caught my eye.

The article described how two independent groups of scientists found evidence that Alzheimer’s disease may spread from brain cell to brain cell much like a virus. These scientists engineered mice to make a human form of a protein called tau in only one small part of the brain. Clumps of the tau protein are a hallmark of Alzheimer’s disease. Like the rubble of demolished buildings, these clumps are all that are left of brains cells that have slowly died because of Alzheimer’s.

Proteins and Clumps

Proteins in the body are folded into special shapes … almost like pieces of origami. Some proteins, if they are not folded correctly to begin with or become “crumpled” due to some cellular problem, will stick together in clumps. Similar to how clumps of the protein tau are a hallmark of Alzheimer’s, clumps of a protein called alpha-synuclein are the hallmark by which Parkinson’s disease is diagnosed. These alpha-synuclein clumps are called Lewy bodies.

Parkinson’s and the Contagion Theory

Parkinson’s researchers have long noted what appears to be the spread of Lewy bodies from one brain region to another. Researchers observed possible clinical evidence that Parkinson’s could “spread” from one cell to another, when fetal cells were transplanted into the brains of people with Parkinson’s disease. The transplants subsequently developed Lewy bodies. That is, something about a Parkinson’s brain made genetically unrelated cells that were only a few years old develop the signs of Parkinson’s disease.

What came out of these observations was the controversial idea that Parkinson’s, once started, might be transmissible from brain cell to brain cell.

Several recent scientific papers are beginning to lend credence to this idea:

• Last year, Dr. Patrik Brundin’s research team in Lund, Sweden published a paper demonstrating that mis-folded alpha-synuclein (the basis of Lewy bodies) can spread from cell to cell in culture and could also spread in the brain of a mouse.
• More recently, Dr. Virginia Lee's team from the University of Pennsylvania published similar findings this past November.
• At a recent New York Academy of Sciences meeting on Parkinson’s disease, unpublished data was presented that also demonstrated how a single injection of alpha-synuclein clumps into a mouse brain could lead to the widespread formation of Lewy bodies in many different parts of the brain.

What Does It Mean?

Well it brings hope that a Parkinson’s therapy might be found in one of two ways: using special antibodies that target alpha-synuclein or a vaccine which primes the immune system to also target alpha-synuclein.

Either approach may not only halt the spread of Parkinson’s disease but maybe could also prevent it.

Your Feedback

What do you think about the recent Alzheimer’s study and how it relates to Parkinson’s? As always, please share your comments and I will do my best to respond.

WPC Science Day Two: Genetics Updates

From James Beck, Ph.D., Director of Research Programs

Here are some additional scientific updates from this week's 2nd World Parkinson Congress (WPC).

Michael Schlossmacher, M.D., reported the results of his recent experiments that demonstrate that mutations in the GBA gene, which were recently identified as a major risk factor for Parkinson's disease (PD), actually contribute to an increase in the levels of alpha-synuclein in nerve cells. Alpha-synuclein is the protein that accumulates in dying nerve cells and is the hallmark of Parkinson’s disease. This result provides a biological explanation as to the significance of these GBA mutations and their relevance to PD. That is to say, Dr. Schlossmacher has shown how mutations in the GBA gene are related to an increased risk of PD. His work has gone through peer review and is currently awaiting publication—we will let you know when it is published and report on his findings in more detail.

Additionally, Haydeh Payami, Ph.D., a research scientist from the Wadsworth Center and Director of the NeuroGenetics Research Consortium in New York State, reported late-breaking results of the re-analysis of a large-scale genetics study her team published this past March in Nature Genetics. The re-analysis examined whether there was a genetic interaction with the onset of Parkinson’s disease and the amount of coffee study participants consumed. Her team found a strong link with a particular gene called GRIN2A, which makes one component of the receptor protein that binds to an important neurotransmitter called glutamate. When this receptor protein binds too much glutamate, it becomes over-activated and can lead to cell death.

What is the role of coffee? Well, the caffeine in coffee indirectly alters how much glutamate is released from neurons by blocking the function of another receptor protein—the adenosine A2A receptor. This in turn, may prevent the cell death observed in the presence of too much glutamate. Indeed, epidemiological evidence suggests that coffee drinkers may have a lower risk of PD. However, Dr. Payami introduced a wrinkle in this concept. She suggests that her teams’s genetic data reveals that only some people may benefit from the strategy of blocking the A2A receptor. You see GRIN2A comes in two forms and only 25 percent of the population have the version which Dr. Payami suggests is beneficial.

Please keep in mind that Dr. Payami's study results were part of a late-breaking science presentation at the WPC, meaning the results were fresh from the lab and will need to be validated and reviewed by her peers. So as compelling as the results are, it will be interesting to see if these findings will stand after a critical examination has been performed. Whether her hypothesis regarding which form of GRIN2A is important is right or wrong, she raised an a critical issue that may be impact future drug discovery—the significance of genetically characterizing research participants. We are all genetically different, so is it so surprising that some people respond better to certain drugs than others? Maybe this is why many drugs fail clinical trials? What do you think?

As the science advances, you can count on PDF to keep you updated.