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The Links Between Gaucher Disease and Parkinson’s Disease (Podcast Recap)

Research into the link between Gaucher disease and Parkinson’s disease may provide answers to treatment for both conditions.

Gaucher Disease and Parkinson’s Diseases: An Unexpected Connection

As Gaucher disease research progresses, scientists are discovering stronger links between the condition and other neurological illnesses, like Parkinson’s disease. But there’s still much to learn about how, and why, these two diseases are interconnected.

In this month’s podcast, we’re talking about the connection between Gaucher disease and Parkinson’s disease, and what it means for you and your family. Joining us is Dr. Roy Alcalay, Assistant Professor of Neurology at Columbia University Medical Center, whose research focuses primarily on the genetic components and biomarkers of Parkinson’s disease. Dr. Alcalay has recently joined the North American Scientific Advisory Board of the International Collaborative Gaucher Group.

Everything You Wanted to Know About Cells But Were Afraid to Ask

Cells are amazingly efficient, microscopic structures in our body that are in a constant process of production, maintenance and recycling. What’s inside of a cell getting all that done?

  • Proteins are a group of large molecules that together with complex lipids are the building blocks of every cell in your body. There are two main types of proteins:
    • Structural proteins maintain and support the structure of each cell and its internal organelles (tiny sub-compartments) such as lysosomes.
    • Enzymes are crucial for starting and accelerating key chemical reactions, allowing each of your cells to function properly.
  • Lysosomes are specialized organelles within each cell that act as “recycling centers.” Over time, molecules in your cells degrade, or deteriorate. When this occurs, lysosomes process these molecules, recycling usable components for reuse within the cell. Different enzymes within lysosomes initiate the breakdown of larger molecules into their reusable components.

What Causes Gaucher Disease and Parkinson’s Disease?

Gaucher disease is a lysosomal storage disease, where one of the key enzymes within the lysosomes, glucocerebrosidase, doesn’t function properly. As a result, lipids, or large, fatty molecules, are not broken down into smaller chemicals. These lipids accumulate first in the lysosomes, then throughout the cells in the body.

Parkinson’s disease is a neurological condition characterized by a steady decline in cognitive and motor function. If you have Parkinson’s disease, cells within your brain, called neurons, stop functioning as well as they did before. Eventually, they degrade and die.

Many neurons use chemicals called neurotransmitters to communicate with each other and with other cells in the brain. In the early stages of Parkinson’s disease, neurons releasing dopamine are affected, leading to insufficient amounts of dopamine in the brain. People begin to develop the symptoms of Parkinson’s disease, such as slowed movements, shuffling or unsteady gait (walk), and resting tremors.

In later stages, patients can develop dementia. This condition is associated with tangles of a protein called synuclein that disrupt neural pathways and affect higher brain functions including memory.

Parkinson’s and Lewy Body Dementia

Parkinson’s disease is often associated with another illness known as Lewy Body Dementia (LBD). If you look at brain tissue under a microscope, it’s difficult to distinguish the cellular changes caused by Parkinson’s disease from those caused by LBD. Doctors typically diagnose LBD based on symptoms: An individual who never exhibits any motor symptoms but develops dementia early on most likely has LBD.

In some cases, people living with LBD will have mild Parkinson’s disease motor symptoms, such as a shuffling gait. People with LBD also tend to hallucinate more, and have a harder time multitasking, compared to people with other neurological diseases, like Alzheimer’s disease.

Is Autophagic-Lysosomal Dysfunction the Parkinson’s-Gaucher Link?

Researchers noticed:

  • A higher likelihood of Parkinson’s disease or Parkinson’s-like symptoms in people diagnosed with type 1 Gaucher disease who are older than 60. However, even by age 80, the risk doesn’t exceed 10%. (The general population risk factor is about 1% in people over 60, and 2% in those over 80).
  • In the parents of people diagnosed with Gaucher disease or other relatives who are known to be Gaucher carriers, there is a higher prevalence of Parkinson’s disease compared to people of a comparable age who do not have Gaucher mutations.

These findings led researchers to identify a physiologic and biochemical connection between the two conditions. That connection is known as “autophagic-lysosomal dysfunction.” The autophagic-lysosomal system is the system in the body responsible for recycling the organelles and proteins. When that system doesn’t work properly, it’s called autophagic-lysosomal dysfunctions. Understand autophagic-lysosomal dysfunction could be the key to better understanding why some people with Gaucher disease also develop Parkinson’s disease.

Most people with type 1 Gaucher disease never develop neurological symptoms. Sometimes, however, slow lifetime accumulation of lipids such as glucocerebroside and glucosylsphingosine seems to promote accumulation of brain proteins such as synuclein. These proteins are associated with onset of Parkinson disease.

Researchers believe that a lysosome problem is at work. Just like with Gaucher disease, the lysosomes of people with Parkinson’s disease don’t work correctly to recycle the cellular components that must constantly be renewed. Scientists call this “dysfunction in autophagy” and are working to figure out why and how this important cellular process goes awry in some people with Gaucher disease and what can be done to fix it.

Current Research Efforts Into Gaucher Disease and Parkinson’s Disease

Today, we have treatments available for:

  • Gaucher disease that can improve non-neurological symptoms of the condition. However, the medication can’t reach the brain because of “the blood-brain barrier.” This barrier serves to protect the brain from damage by chemicals. Unfortunately, the blood-brain barrier also limits our ability to successfully deliver beneficial drug treatments to the brain.
  • Parkinson’s disease that can improve the motor symptoms but don’t appear to prevent inevitable disease progression.

Finding a treatment that permeates the brain to relieve the severe neurological symptoms that affect patients with type 2 and with type 3 Gaucher disease is a high research priority. Clinical trials currently investigating these treatments include:

  • Testing a new drug that can reduce biosynthesis of glucocerebroside in the brain. If we can slow the accumulation of this lipid in the brain, it might relieve the neurological symptoms of Gaucher disease. Although this trial focuses on patients with type 3 Gaucher disease, a positive result might also indicate a role for the test drug in preventing or treating Parkinson’s disease in patients with type 1 Gaucher disease.
  • Testing a different drug whose function is to increase brain glucocerebrosidase activity in patients with Parkinson disease, including those who are Gaucher carriers. Glucocerebrosidase is the critical enzyme that helps break down and recycle the molecules, which doesn’t function properly in people with Gaucher disease.
  • Investigating modifications to the Gaucher disease pathway in the brain to help slow down or prevent Parkinson’s disease.

There is a high level of interest in these trials from the scientific and public health communities, indicated by the funding institutions: National Institutes of Health, the Parkinson’s Disease Foundation, and the Michael J. Fox Foundation.

Parkinson’s disease and Alzheimer’s disease

Some scientists wonder if there’s a connection between Parkinson’s disease and Alzheimer’s disease. Both are neurological conditions causing cells in the brain to degenerate over time. But they cause different types of proteins to accumulate in the brain cells. In Alzheimer’s disease, these proteins are known as amyloid beta and tau. In Parkinson’s disease, the protein is called alpha-synuclein.

Research is focusing on ways to differentiate between the cognitive impairments associated with Parkinson’s disease and those associated with Alzheimer’s disease. We know that people with Parkinson’s disease usually don’t display language and memory impairment the way people with Alzheimer’s disease do. However, we need further research to understand the possible connections between the two illnesses.

It’s fascinating that a rare disorder like Gaucher disease potentially has critical relevance to the two most common neurodegenerative disease that affect so many individuals worldwide.

The Immune System’s Role

Researchers are focusing on the role of a specific type of immune system cell, called a macrophage, in both Parkinson’s disease and Gaucher disease. Scientists are researching the effect of the immune system on Parkinson’s disease, trying to better understand the interactions. The goal is to develop treatments that modify the immune system, using certain immune system cells to block the accumulation of alpha-synuclein. Scientists are hoping this immune system research will advance the understanding and treatment of Gaucher disease as well.

Glucocerebrosidase (GBA) Mutations

Gaucher disease is caused by mutations in the gene that directs production of the enzyme glucocerebrosidase (GBA1 mutations). GBA1 mutations are also more common in people with Parkinson’s disease compared to those who don’t have the disease.

As many as 10% of people with Parkinson’s disease carry GBA1 mutations in their genes, suggesting that GBA1 mutations are an important genetic risk factor for the development of Parkinson disease even in people who don’t have Gaucher disease In fact, having a GBA1 mutation is currently the leading genetic risk factor for developing Parkinson disease.

GBA mutations in carriers also lead to a reduction in the amount of intracellular glucocerebrosidase, although not to an extent sufficient to cause Gaucher disease itself. However, even minor reduction in glucocerebrosidase activity can have an effect. This reduction may promote synuclein deposition and chemical injury in specific brain neurons whose normal function is needed to prevent Parkinson disease from emerging.

Another theory is that structural abnormalities in the glucocerebrosidase that is coded for by mutant GBA1 genes can also lead to neuronoal injury and even to early cell death (apoptosis). Perhaps both theories are correct. Further research will lead to a better understanding of how defects in GBA1 are related to Parkinson’s disease.

The Effect of Personalized Medicine

Personalized, or precision, medicine is a treatment plan that doctors customize to your specific needs. Your genetic makeup is an important but not exclusive contributor to who you are. Epigenetics (chemicals that control gene function) also plays an important role in “who you are” as you grow, develop, mature and age. Environmental influences have an effect as well. As interest in personalized medicine grows, researchers are developing new studies and treatments. In the past, scientists conducted research assuming that everyone would respond similarly to treatment.

Now we understand that individuals respond differently to treatments. The personalized medicine approach dictates that scientists, physicians and allied health care professionals tailor treatments to specific individual need.

This approach is especially important for a disease like Parkinson’s disease. Scientists have already identified more than 20 different genes linked to Parkinson’s disease. While they’re all associated with the condition, people with different genetic profiles have different experiences living with the disease.

Because of the complex connections between Gaucher disease and Parkinson’s disease, this may be a unique opportunity to apply the principles of personalized medicine to treat these conditions. Instead of blanket therapies, doctors could identify people with Parkinson’s disease who also have Gaucher mutations. Then, those people could receive treatments that enhance Gaucher gene pathways. Other Parkinson’s patients may need dopamine replacement therapy.

The type of treatment will depend heavily on the individual and their specific symptoms.

Personalized medicine can influence our country’s national health policy. For personalized medicine to work, doctors must analyze an individual’s genetic data. But sharing that data to guide treatment raises many questions about personal privacy. For example, where would we store information about an individual’s genes, and who would have access to that information? This is a work in progress that must be the topic of further discussion.

Gaucher and Parkinson’s: Where Do We Go from Here?

Scientists can’t predict all the risk factors leading to Parkinson’s disease, but they have identified some non-modifiable risk factors. Men are at much higher risk for the disease, as are people age 70 and older.

What is the future of Gaucher-Parkinson’s research?

  • Risk for developing Parkinson’s disease: While most people living with Gaucher disease never develop Parkinson’s disease, you may want to know what your risk is if you’ve been diagnosed with Gaucher disease. Using data from the Gaucher disease patient registry, one study estimates that only about 10% of those with Gaucher disease type 1 develop Parkinson’s disease in their lifetime. But we need more research to confirm these results and to estimate Parkinson’s disease rates among people with Gaucher disease type 3, some of whom can live to middle age or even beyond with effective treatment.
  • Family health: You may want to know if you are a carrier of the mutations causing Gaucher disease and Parkinson’s disease. If you are a carrier for Gaucher disease, and you have a family member with Parkinson’s disease, what should you know about your health and the health of your children? This is something you should discuss with a Gaucher disease specialist.
  • Carrier status: Currently, doctors don’t test people with Parkinson’s disease for the GBA mutations that cause Gaucher disease. However, it is likely that DNA analysis for GBA1 mutations (with either blood spots or saliva) may become a common test for people with a Parkinson disease diagnosis or for their family members. As a result, more GBA1 carriers may be identified in both the Ashkenazi Jewish and non-Jewish populations as well as individuals with actual Gaucher disease itself. This may change our perception of the prevalence of GBA1 mutations and could be a further impetus for including Gaucher disease testing in the panels for newborn screening.

The evolving story of the relationship between GBA1 mutations, Gaucher disease and Parkinson disease will undoubtedly be the subject of ongoing basic and clinical research that will require the participation of the Gaucher disease community. Participating in research and clinical trials is an excellent way to improve care for these two conditions.


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