By Alexis Park ‘28

Parkinson’s disease (PD) is classified as a chronic neurodegenerative disorder that hinders movement and balance (Parkinson’s Foundation). As the second most common neurodegenerative disorder in the United States, neurological causes for PD range from genetic factors to dysregulated protein degradation, with one prominent explanation being dopamine deficiency caused by a disorder of nerve cells.

The pathological hallmark of PD is explained by the distribution of Lewy bodies throughout the brain. Lewy bodies, intracellular cytoplasmic inclusions, typically of a spherical shape, cause a form of dementia called Lewy body dementia (LBD) when accumulated in the brain (Doty 2012). With the exception of a small subset of PD patients whose condition stemmed from a specific genetic mutation, it is the lewy body clusters that cause some to all of the motor symptoms of PD. While LBD and PD are different diseases, the symptoms that those affected face are similar, which can explain memory or cognitive problems and visual hallucinations that PD patients can encounter. However, due to clinical overlap with other neurodegenerative conditions, disease diagnosis for Parkinson’s is indefinitive based on a single test, such as MRI imaging, and a patient’s medical history, neurological examination, medication response, and symptoms must all be taken into consideration. Heiko Braak, a German pathologist, is known for his hypothesis on PD that states a pathogen enters the body via the nasal cavity, is swallowed, and reaches the gut to initiate Lewy pathology (LP) in the nose and the digestive tract. While this spread is not supported in all cases, recent research does suggest cell-to-cell transmission and synuclein template facilitation are key mechanisms in PD progression. 

Lewy bodies are also associated with blocking certain neurotransmitters in the brain, such as dopamine. Dopamine is a key neurotransmitter in movement and muscle control, explaining the hallmark symptoms of motor impairment seen in Parkinson’s patients. Risk factors that cause dopamine degeneration can subsequently lead to PD. For example, as explained by John V. Hindle in Age and Ageing, age is one of the largest risk factors for the development of Parkinson’s disease as it affects many cellular processes that predispose an individual to neurodegeneration, and therefore dopamine degeneration (Hindle, 2010).  

Recently, the receptor Guanylyl cyclase C (GUCY2C) has been identified as a potential way to fight dopamine loss. GUCY2C was first discovered and characterized in the 1970s as a receptor for heat-stable enterotoxin, which is produced by diarrheagenic enteric bacteria. Originally found in the intestinal epithelium, regulating intestinal homeostasis and electrolyte secretion, GUCY2C has recently been found in the substantia nigra, an area of the brain that produces dopamine and is targeted by PD (Waldman, 2022). Other areas the receptor has been expressed includes the hypothalamus, ventral tegmental area, and nigrostriatal pathway. As opposed to their function in the intestine, within the substantia nigra, GUCY2C and their second messenger cGMP supports mitochondrial function to protect against reactive oxygen species and promote cell survival. GUCY2C is also found as a defense to protect the dopamine neurons in the brain, although it remains unclear how its presence defines the vulnerability of dopaminergic neurons in the substantia nigra for Parkinson’s patients.This uncertainty lies in the challenge of selectively manipulating GUCY2C’s cGMP levels, which as a second messenger, is responsible for relaying signals to intracellular components (Newton, 2016). 

A study led by Scott Waldman, MD, PhD, demonstrated how GUCY2C signaling can help mitigate Parkinson’s disease through a 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) mouse model. MPTP exposure in the model was used to replicate PD symptoms, especially in regard to dopaminergic neuron loss. The researchers activated GUCY2C signaling in the mice, and in doing so, found that the loss of GUCY2C leads to mitochondrial dysfunction and oxidative stress within the nigrostriatal pathway. To the genetically modified mice in which the GUCY2C gene was knocked out, a standard dose of MPTP proved to be lethal. Additionally, conditionally eliminating GUCY2C only in the intestine did not result in increased dopaminergic neuron vulnerability, but when reversed, neuroprotective effects found in the substantia nigra were lost. While there is evidence suggesting decreased GUCY2C protein levels caused by PD, additional data from mice treated with MPTP revealed that GUCY2C mRNA is overexpressed in PD pathology. The overproduction of GUCY2C mRNA can cause cellular damage in attempting to compensate for protein loss. 

Waldman’s study is the first to recognize the receptor GUCY2C as a possible defense mechanism against dopamine degeneration. Researchers have begun to identify treatment that involves these findings. One possibility involves augmenting the amount of cGMP, a byproduct of GUCY2C activation to prevent the dopamine loss, along with other genetic and pharmacological activations of GUCY2C. As a protein, GUCY2C is continuously being studied as a therapeutic target for other diseases. Recently, it has also been identified as a biomarker to target precision therapies for patients with colorectal cancer, and due to its association with the gut, can contribute to a growing understanding of the gut-brain axis. Waldman’s study of the receptor protein as a possible defense mechanism against dopamine loss represents the therapeutic potential of GUCY2C, and an avenue of hope for Parkinson’s patients. 

Edited by Sachi Badola ‘26

Sources

Arias, O., & González, M. G. (2017, February 13). Exploring Braak’s Hypothesis of Parkinson’s Disease – PMC. PubMed Central. Retrieved January 2, 2025, from https://pmc.ncbi.nlm.nih.gov/articles/PMC5304413/

Cedars-Sinai Staff. (2017, April 27). Dopamine & Parkinson’s Disease: The Link Between. Cedars-Sinai. Retrieved January 2, 2025, from https://www.cedars-sinai.org/blog/exploring-the-link-between-dopamine-and-parkinsons-disease.html

Doty, R. (2012). Lewy Body. ScienceDirect. https://www.sciencedirect.com/topics/neuroscience/lewy-body#:~:text=Lewy%20body%20disease%20(LBD)%20is,bodies%20(McKeith%2C%202006).

Hindle, J. (2010). Ageing, neurodegeneration and Parkinson’s disease. Age and Ageing, 39(2), 156–161. https://doi.org/10.1093/ageing/afp223

How Parkinson’s Disease Is Diagnosed. (n.d.). Johns Hopkins Medicine. Retrieved January 2, 2025, from https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/how-parkinson-disease-is-diagnosed

Lewy Body Dementia (LBD). (n.d.). Johns Hopkins Medicine. Retrieved January 2, 2025, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/dementia/dementia-with-lewy-bodies

Lisby, A. N., & Flickinger, J. C. (2022, January 1). GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. NIH. https://pmc.ncbi.nlm.nih.gov/articles/PMC8133521/

Newton, A. C. (2016). Second Messengers. PMC. Retrieved January 2, 2025, from https://pmc.ncbi.nlm.nih.gov/articles/PMC4968160/

Parkinson’s Foundation. (n.d.). What is Parkinson’s? Parkinson’s Foundation. Retrieved January 2, 2025, from https://www.parkinson.org/understanding-parkinsons/what-is-parkinsons

Tolosa, E., Garrido, A., & Scholz, S. (2021, May 1). Challenges in the diagnosis of Parkinson’s disease. PubMed Central. Retrieved January 2, 2025, from https://pmc.ncbi.nlm.nih.gov/articles/PMC8185633/

Waldman, S. A. (2022). Guanylyl Cyclase 2C (GUCY2C) in Gastrointestinal Cancers: Recent Innovations and Therapeutic Potential. NIH. Retrieved January 2, 2025, from https://pmc.ncbi.nlm.nih.gov/articles/PMC8363580/

Image Reference: https://www.neurotherapyindia.com/diseases/parkinsons-disease/