A Common Thread in Many Neurodegenerative Diseases: Could it Lead to Breakthrough Therapies?

Learn about my summer research project

A single process occurs in the diseased cells of the four most common neurodegenerative disorders: Alzheimer’s, Parkinson’s, Huntington’s, and ALS. Scientists suggest that successfully researching it could lead to a preventative therapy for these conditions. In today’s article, I explain the importance of this process in brain functioning and justify why it should continue to be studied

I’m delighted to share that I am working on this topic as part of my summer internship at UC San Diego (UCSD). My research over the past three years, conducted at both UCSD and the University of Oregon, has focused on Alzheimer’s disease (AD) and memory. I hope that this piece enlightens you on the hard work being done to cure these diseases.

The Importance of Palmitoylation

Palmitoylation is a protein modification that plays a critical role in neuronal function. Palmitoylation is a key player in neurodevelopment, as it facilitates the growth of axons and dendrites, the signal propagators and receptors of neurons. In addition, palmitoylation helps regulate synapses and promotes plasticity, the process by which neurons adapt and grow to increase healthy brain functioning.

This process occurs in a constant cycle (palmitoylation and depalmitoylation). If this cycle goes out of balance, more palmitoylation than depalmitoylation or vice versa, neurons cannot function properly. Constant disruption to this cycle suggests it can be a pathological mechanism for developing neurodegenerative diseases.

A Deeper Dive

Read the section below for a more thorough understanding of palmitoylation:

Palmitoylation is a posttranslational protein modification where a palmitic acid (a long, saturated fatty acid) is attached to a protein’s cysteine residue via a thioester bond. It is the only reversible lipid modification, meaning it can rapidly adapt protein function in response to stimulation. Lipid modifications increase the protein’s affinity for nonpolar structures, leading to increased hydrophobicity and altered protein stability, trafficking, and associations with organelles and membranes. Thereby, changing a synapse’s structure and activity.

Credits to: Journal of Neuroscience, “Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders”

Palmitoylation Examples in Many Neurodegenerative Diseases

Palmitoylation either directly or indirectly impacts the many biomarkers of common neurodegenerative diseases. Amyloid-beta and tau in Alzheimer’s Disease, alpha-synuclein in Parkinson’s Disease, the HTT protein in Huntington’s Disease, and the SOD1 enzyme in Huntington’s (Read more about biomarkers here.)

In Alzheimer’s, amyloid precursor protein (APP), a building block of amyloid-beta, is palmitoylated (along with a few enzymes) to create amyloid-beta. Specifically, this leads to the creation of the most neurotoxic species of a-beta.

An Ideal Drug Therapy

What does a solution by manipulating palmitoylation look like?

The goal would be to develop a drug that regulates the cycle of these processes, such that palmitoylation and de-palmitoylation occur at altered rates. An example is changing the rate of the enzymes that carry out this cycle, which has shown promising results in many animal models and cell cultures with AD, HD, and PD. Specifically in AD, increasing the quantity of a protein that upregulates palmitoylation blocked the effects of a-beta on synapses.

The commonality of palmitoylation across the four most common neurodegenerative diseases cannot be overlooked. Considering how each neurodegenerative disease manifests so differently, finding common ground can help us gain a broader understanding of neurodegenerative diseases as a whole. A drug developed to target one disease may even have a positive effect on another disease.

There are, of course, many challenges ahead. Scientists need to develop a deeper understanding of how palmitoylation broadly affects neurons and address the deficits created by the cycle change. Currently, technology and methodology are unable to detect palmitoylation in a timely and accurate manner. Several proteins and enzymes utilize this process, so a highly sophisticated and specific drug must be developed to not interfere with other important processes.

Potential Impacts

Let’s take Alzheimer’s Disease for example. The current treatments (check out this post for more information) target amyloid-beta, slowing cognitive decline over time. A drug working to regulate the palmitoylation cycle may prevent amyloid-beta from ever building up. An ideal drug could be preventive; those with a genetic history and fear of cognitive decline could begin taking it around the age of early-onset for Alzheimer's (~30-40 years old).

My idealized drug would be far more preventive, where those with a fear of cognitive decline and a genetic history could start taking it before symptoms occur.

A regulatory drug could even be used universally across all patients with a history of any neurodegenerative disease. Fighting the biomarkers (read more here) of all neurodegenerative diseases at once could be the ultimate drug. Although many years of research lie ahead, scientists continue to develop new “ins” to target neurodegenerative diseases.

My Role

I am thrilled to work at UCSD this summer and help contribute to an important issue. I am working alongside my mentor to understand the changes in long-term potentiation (LTP), the strengthening of synapses, within hippocampal neurons of AD mice. These mouse models have a knockdown gene that is involved in depalmitoylating a structural protein, resulting in increased palmitoylation and enhanced synaptic strength. The presence of this gene (ABHD17a) has been suggested to prolong the diagnosis of AD by six years. We hope to discover that neurons with AD will be rescued by this increase in palmitoylation, leading to greater synaptic plasticity.

Specifically, I’ll be conducting electrophysiology trials using field recordings to analyze the electrical activity that occurs around neurons when they are stimulated. This can provide insight into how neuronal function changes in mice with an amyloid-beta genotype.

Thank you for reading this week’s article, a topic so close to my work and interests. Stay tuned for future news on all things neuroscience.

Sources

Dore, K., Carrico, Z., Alfonso, S., Marino, M., Koymans, K., Kessels, H. W., & Malinow, R. (2021). PSD-95 protects synapses from β-amyloid. Cell Reports, 35(9), 109194. https://doi.org/10.1016/j.celrep.2021.109194

Wlodarczyk, J., Bhattacharyya, R., Dore, K., Ho, G. P. H., Martin, D. D. O., Mejias, R., & Hochrainer, K. (2024). Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders. Journal of Neuroscience, 44(40). https://doi.org/10.1523/JNEUROSCI.1225-24.2024