Guanylyl cyclase C (GUCY2C) is protective against dopamine neuron degeneration, a hallmark of Parkinson’s, by helping the cell’s powerhouse.

A new study is the first to identify a brain receptor called GUCY2C as a potential way to fight dopamine loss.

Parkinson’s disease (PD) is caused by the death of neurons that produce dopamine — a feel-good chemical related to movement, mood and more — in the brain. Dopamine neurons are involved in movement and the loss of these neurons disrupts the brain's ability to regulate movement, leading to hallmark PD symptoms, such as tremors, rigidity and slowness.

One of the reasons that dopamine neurons die is due to dysfunction of mitochondria, the small oxygen-consuming and energy-producing powerhouses inside cells. Recent research has found a receptor on the surfaces of those Parkinson’s-associated dopamine neurons that may provide therapeutic ways to protect the mitochondria and prevent the progression of the disease.

The receptor, called guanylyl cyclase C (GUCY2C), was first discovered on the surfaces of cells in the intestine, but was recently found in a region of the brain called the substantia nigra pars compacta (SNpc). This area of the brain is affected in PD.

A new study led by Scott Waldman, MD, PhD, and funded by the Parkinson’s Foundation 2023 Impact Award, gives a clearer picture of how GUCY2C signaling can provide protection against mitochondrial dysregulation and dopamine neuron degeneration that leads to PD. According to the study, in people with Parkinson’s, dopamine neurons make extra GUCY2C receptors.

About the Study & Results

Dr. Waldman and his team studied mice with and without the GUCY2C receptor. They found that loss of GUCY2C led to mitochondrial dysfunction, oxidative stress and cell death within the part of the brain impacted by PD, suggesting a protective nature of GUCY2C.

When the researchers gave the two groups of mice a toxin that induces PD symptoms by targeting mitochondria in dopamine neurons, only mice that did not have GUCY2C receptors had higher rates of dopamine neuron death. In contrast, mice with GUCY2C increased their production of the protein upon treatment with the toxin, further indicating a protective role.

The researchers also found that cyclic GMP (cGMP), a byproduct of GUCY2C activation, protected dopamine neurons from oxidative stress. In neurons grown in a petri dish, adding a molecule that increases cGMP protected dopamine neurons from oxidative stress and mitochondrial dysfunction when they added the PD-inducing toxin.

These results indicate that in Parkinson’s disease, the increase in GUCY2C might be the body's attempt to protect dopamine neurons from damage. It may be possible to develop a molecule that targets GUCY2C or use existing drugs that increase cGMP to protect dopamine neurons from damage.

Highlights

• Loss of the receptor GUCY2C led to dopamine neuron degeneration in mice — in other words, not having the GUCY2C receptor led to neuronal dysfunction in brain regions implicated in PD.
• A molecule that increases cGMP (a byproduct of GUCY2C activation) protected neurons grown in a petri dish from mitochondrial dysfunction and cell death when the researchers added a toxin that induces neurodegeneration.
• Because GUCY2C is increased in people with Parkinson’s, the study results suggest that the increase in GUCY2C may be the body's attempt to protect dopamine neurons from damage.

What does this mean?

This study is the first to identify the receptor GUCY2C as a possible defense mechanism against dopamine loss. This research marks the beginning of what can be a new way to significantly slow down the progression of Parkinson’s.

Since GUCY2C appears to protect dopamine neurons in the brain, researchers could explore the possibility of stimulating GUCY2C as a treatment for PD. They could also try increasing cGMP, a byproduct of GUCY2C activation. This could potentially prevent the degeneration of dopamine neurons, a hallmark of the disease.

The study also found that people with PD have high levels of GUCY2C, which may also serve as an early indicator of Parkinson’s.

What do these findings mean to the people with PD right now?

With more research, GUCY2C could be a potential biomarker doctors can use to detect PD earlier. Having access to early biomarkers are critical for early therapeutic interventions for people with PD.

In addition, GUCY2C is a promising therapeutic target to prevent or treat PD. While developing a treatment that targets GUCY2C or its byproducts could take time, it remains important for researchers to identify as many potential treatments as possible. People who are currently experiencing Parkinson’s symptoms should talk to a healthcare provider.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about PD and the topics in this article through our below resources, or by calling our free Helpline at 1-800-4PD-INFO (1-800-473-4636) for answers to your Parkinson’s questions.

• My PD Story: Scott Waldman, MD, PhD – learn more about this study and Dr. Waldman
• Neuro Talk: PD Progression
• Getting Diagnosed

What can you expect as Parkinson’s disease (PD) progresses? What are the signs and symptoms of each stage? Although the loss of dopamine is universal for people with PD,  each person experiences a unique combination of movement and non-movement symptoms and disease progression. 

In our latest Neuro Talk, Chief Scientific Officer James Beck, PhD, discusses the different stages of Parkinson’s disease progression and strategies for living well.

For most people, being in the hospital is a stressful experience. People are usually sick or experiencing a health issue. For people with Parkinson’s disease (PD), their symptoms may get worse, and new symptoms, like confusion or thinking changes, can develop because of stress, infection, fatigue, sleep disturbances, surgery or new medications.

A new published review of more than 35,000 hospital admissions of people with Parkinson’s found an increased risk of delirium and aspiration pneumonia as potentially avoidable complications. 

As we share in our Hospital Safety Guide, preparation and clear communication can help you minimize complications and recovery time when hospitalized. Understanding the risks you or a loved one with Parkinson’s face and ways to have your needs met can help the hospital care team provide the best possible care. 

Know how to identify Delirium

Delirium is a reversible change in a person's level of attention and concentration. 

Anti-nausea, gastrointestinal and pain medications, which are routinely given before and after surgery, can worsen existing PD symptoms or cause new, temporary symptoms like delirium. Avoiding these medications can decrease your risk of developing delirium.

Additionally, some common treatments for delirium aren’t appropriate for people with PD, and can make Parkinson’s symptoms and the delirium worse. If you or a loved one develop delirium in the hospital, it is important to avoid the antipsychotic medications that are antidopaminergic, meaning they decrease the amount of dopamine in the brain. 

People with Parkinson’s should only be given one of the three antipsychotics that are safe: 

1. Pimavanserin (Nuplazid)
2. Quetiapine (Seroquel)
3. Clozapine (Clozaril). 

All psychotics, with the exception of these three, should be avoided in nearly all circumstances.

Read our list of medications to avoid

Know the signs of Aspiration Pneumonia 

Aspiration pneumonia accounts for 70% of deaths among people with PD, according to an NIH study. 

Aspiration pneumonia is an infection that happens when bacteria from your mouth gets pulled down into the lungs and causes an infection. This can happen after a person aspirates, meaning they swallow the wrong way, and something enters their airways or lungs. Aspiration occurs more frequently when someone has issues with swallowing (dysphagia), which is a common Parkinson’s symptom. 

To prevent aspiration and aspiration pneumonia, people with Parkinson’s need to be screened for swallowing changes, also known as dysphagia, to safely maintain their medication routine and minimize their risk of aspiration pneumonia and weight loss. 

In addition, ensuring that you or your loved one with Parkinson’s get their Parkinson’s medications on time and avoid contraindicated medications that are not safe for people with Parkinson’s can also help prevent the development of new dysphagia or the worsening of mild dysphagia. 

Tips to avoid delirium and aspiration pneumonia in the hospital

Tip 1.  Avoid medications that are not safe for Parkinson’s. 

This can potentially help you to:

• Prevent delirium caused by taking contraindicated anti-nausea medications
• Prevent worsening of delirium caused by taking contraindicated antipsychotic medications

Review the list of harmful medications on the Parkinson’s Care Summary with your hospital care team before surgery and before any new medication is prescribed.

Tip 2. Take medications on time, every time to help prevent new or worsening swallowing challenges. 

If your nurse or speech-language pathologist is concerned about your swallowing ability, discuss safe ways to continue taking your medications, such as with a sip of water or crushed with applesauce.

Use the Medication Form to list all your medications for Parkinson’s and other conditions, including over-the counter medications and supplements in the order that you take them each day. Your list should be clearly labeled with the dosage (usually mg or milligrams) and the specific time that you take each medication.

Download the Medication Form

Tip 3. Tell your nurses if you are having trouble swallowing and ask to see the Speech Language Pathologist (SLP). 

Together, your nurse and SLP can provide safety measures to decrease risks.

You may need to temporarily stop eating and drinking if you have a serious swallowing issue (dysphagia) or are scheduled for a medical procedure that requires fasting. If you or your loved one are instructed you cannot swallow pills, show the nurse and SLP “Other Ways to Take your Medication” to explore potential ways to safely continue taking Parkinson’s medications

If you have swallowing or speech symptoms, we recommend you regularly see a speech language pathologist. Once discharged, ask your doctor for a referral, or call our Helpline at 1-800-4PD-INFO (1-800-473-4636).

Tip 4. Reducing the risk of aspiration pneumonia is a two-part process.

Help reduce aspiration pneumonia when hospitalized and at home that involves (1) preventing swallowing issues and (2) reducing bacteria in your mouth by cleaning your teeth and mouth regularly. Learn more about dental health and Parkinson’s.

Prevent aspiration by eating when PD meds are working and you have energy. It can also help to sit up for meals and take smaller bites. Prevent aspiration pneumonia by brushing your teeth, tongue and mouth before and after eating to reduce bacteria. 

Read more about the steps you can take to avoid delirium, aspiration pneumonia, and other avoidable complications in our Hospital Safety Guide.

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